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Revisiting skeletal myopathy and exercise training in heart failure: Emerging role of myokines

  • Author Footnotes
    1 Both authors contributed equally to this work.
    Robinson Ramírez-Vélez
    Footnotes
    1 Both authors contributed equally to this work.
    Affiliations
    Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Spain

    CIBERFES, Carlos III Institute of Health, Madrid, Spain

    Institute for Health Research of Navarra (IDISNA), Pamplona, Spain
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  • Author Footnotes
    1 Both authors contributed equally to this work.
    Arantxa González
    Footnotes
    1 Both authors contributed equally to this work.
    Affiliations
    Institute for Health Research of Navarra (IDISNA), Pamplona, Spain

    Program of Cardiovascular Diseases, Center of Applied Medical Research (CIMA), Universidad deNavarra, Pamplona, Spain

    CIBERCV, Carlos III Institute of Health, Madrid, Spain
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  • Antonio García-Hermoso
    Affiliations
    Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Spain

    CIBERFES, Carlos III Institute of Health, Madrid, Spain

    Institute for Health Research of Navarra (IDISNA), Pamplona, Spain
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  • Iñigo Latasa Amézqueta
    Affiliations
    Program of Cardiovascular Diseases, Center of Applied Medical Research (CIMA), Universidad deNavarra, Pamplona, Spain
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  • Author Footnotes
    2 Both authors jointly supervised this work.
    Mikel Izquierdo
    Correspondence
    Correspondence to: M. Izquierdo, Department of Health Sciences, Navarrabiomed, Public University of Navarra, Irunlarrea 3, Complejo Hospitalario de Navarra, 31008 Pamplona, Navarra, Spain.
    Footnotes
    2 Both authors jointly supervised this work.
    Affiliations
    Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Spain

    CIBERFES, Carlos III Institute of Health, Madrid, Spain

    Institute for Health Research of Navarra (IDISNA), Pamplona, Spain
    Search for articles by this author
  • Author Footnotes
    2 Both authors jointly supervised this work.
    Javier Díez
    Correspondence
    Correspondence to: J. Díez, Program of Cardiovascular Diseases, CIMA, Universidad de Navarra, Pío XII 55, 31008 Pamplona, Spain.
    Footnotes
    2 Both authors jointly supervised this work.
    Affiliations
    Institute for Health Research of Navarra (IDISNA), Pamplona, Spain

    Program of Cardiovascular Diseases, Center of Applied Medical Research (CIMA), Universidad deNavarra, Pamplona, Spain

    CIBERCV, Carlos III Institute of Health, Madrid, Spain
    Search for articles by this author
  • Author Footnotes
    1 Both authors contributed equally to this work.
    2 Both authors jointly supervised this work.
Open AccessPublished:November 17, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155348

      Highlights

      • Myokines are molecules synthesized and secreted by skeletal muscle in response to physical exercise.
      • Myokines may provide new insights into some aspects of heart failure-related skeletal myopathy.
      • Myokines may exert beneficial or detrimental effects on cardiac structure and function in heart failure.
      • Myokines may be useful as potential biomarkers to personalize physical training in heart failure.

      Abstract

      Exercise intolerance remains a major unmet medical need in patients with heart failure (HF). Skeletal myopathy is currently considered as the major limiting factor for exercise capacity in HF patients. On the other hand, emerging evidence suggest that physical exercise can decrease morbidity and mortality in HF patients. Therefore, mechanistic insights into skeletal myopathy may uncover critical aspects for therapeutic interventions to improve exercise performance in HF. Emerging data reviewed in this article suggest that the assessment of circulating myokines (molecules synthesized and secreted by skeletal muscle in response to contraction that display autocrine, paracrine and endocrine actions) may provide new insights into the pathophysiology, phenotyping and prognostic stratification of HF-related skeletal myopathy. Further studies are required to determine whether myokines may also serve as biomarkers to personalize the modality and dose of physical training prescribed for patients with HF and exercise intolerance. In addition, the production and secretion of myokines in patients with HF may interact with systemic alterations (e.g., inflammation and metabolic disturbances), frequently present in patients with HF. Furthermore, myokines may exert beneficial or detrimental effects on cardiac structure and function, which may influence adverse cardiac remodelling and clinical outcomes in HF patients. Collectively, these data suggest that a deeper knowledge on myokines regulation and actions may lead to the identification of novel physical exercise-based therapeutic approaches for HF patients.

      Graphical abstract

      Keywords

      1. Introduction

      Exercise intolerance, defined as an impairment in the capacity to perform physical exercise accompanied by symptoms of significant dyspnea and/or fatigue, is the cardinal manifestation of heart failure (HF) and is associated with reduced quality of life (QoL) and poor prognosis [
      • Del Buono M.G.
      • Arena R.
      • Borlaug B.A.
      • Carbone S.
      • Canada J.M.
      • Kirkman D.L.
      • et al.
      Exercise intolerance in patients with heart failure: JACC state-of-the-art review.
      ,
      • Pandey A.
      • Shah S.J.
      • Butler J.
      • Kellogg Jr., D.L.
      • Lewis G.D.
      • Formanet D.E.
      • et al.
      Exercise intolerance in older adults with heart failure with preserved ejection fraction: JACC state-of-the-art review.
      ]. The determinants of reduced exercise capacity in patients with HF are multiple and include impaired cardiovascular and pulmonary reserve and structural and functional skeletal muscle abnormalities (i.e., skeletal myopathy), among others [
      • Del Buono M.G.
      • Arena R.
      • Borlaug B.A.
      • Carbone S.
      • Canada J.M.
      • Kirkman D.L.
      • et al.
      Exercise intolerance in patients with heart failure: JACC state-of-the-art review.
      ]. Additionally, most HF patients are elderly, in whom exercise intolerance secondary to skeletal muscle wasting and sarcopenia (i.e., loss of muscle mass) is part of the aging process [
      • Von Haehling S.
      • Ebner N.
      • Dos Santos M.R.
      • Springer J.
      • Anker S.D.
      Muscle wasting and cachexia in heart failure: mechanisms and therapies.
      ]. Somewhat surprisingly, the degree of exercise intolerance and the severity of accompanying symptoms are not directly related to the degree of cardio-pulmonary weakness in HF patients, but are often related to abnormalities in skeletal musculature [
      • Philippou A.
      • Xanthis D.
      • Chryssanthopοulos C.
      • Maridaki M.
      • Koutsilieris M.
      Heart failure–induced skeletal muscle wasting.
      ]. While many classical and novel HF drugs that reduce hospitalizations and mortality also influence exercise capacity, the magnitude of improvement is modest and variable [
      • von Haehling S.
      • Arzt M.
      • Doehner W.
      • Edelmann F.
      • Evertz R.
      • Ebner N.
      • et al.
      Improving exercise capacity and quality of life using non-invasive heart failure treatments: evidence from clinical trials.
      ]. On the other hand, preserving muscle functional capacity in patients with HF through physical exercise appears to be associated with a lower risk of cardiovascular and all-cause mortality [
      • Aggarwal M.
      • Bozkurt B.
      • Panjrath G.
      • Aggarwal B.
      • Ostfeld R.J.
      • Barnard N.D.
      • Gaggin H.
      • Freeman A.M.
      • Allen K.
      • Madan S.
      • Massera D.
      • Litwin S.E.
      American College of Cardiology's Nutrition and Lifestyle Committee of the Prevention of Cardiovascular Disease Council. Lifestyle modifications for preventing and treating heart failure.
      ]. However, exercise tolerance and activity levels of HF patients remain low [
      • Bozkurt B.
      • Fonarow G.C.
      • Goldberg L.R.
      • Guglin M.
      • Josephson R.A.
      • Formanet D.E.
      • et al.
      Cardiac rehabilitation for patients with heart failure: JACC expert panel.
      ].
      Identifying the mechanisms by which exercise improves physical tolerance and HF prognosis in patients with HF may reinforce the therapeutic role of training and contribute to a better individualization of its prescription in this patient population. Recently, it has been proposed that the underlying mechanistic pathways of the beneficial effects of exercise in HF involve skeletal muscle hypertrophy and enhanced mitochondrial quality control, as well as reversal of histological and macroscopic adverse cardiac remodelling [
      • Nijholt K.T.
      • Sánchez-Aguilera P.I.
      • Voorrips S.N.
      • Boer R.A.
      • Westenbrink B.D.
      Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?.
      ]. In this conceptual framework, we will review several issues related to a complementary and emerging view of skeletal myopathy as an active player in in the pathophysiology and clinical evolution of HF through the dysregulation of myokines. The myokines, term coined in 2003 [
      • Pedersen B.K.
      • Steensberg A.
      • Fischer C.
      • Keller C.
      • Keller P.
      • Plomgaard P.
      • et al.
      Searching for the exercise factor: is IL-6 a candidate?.
      ], belong to a group of factors secreted into circulation by many tissues in response to exercise and known as “exerkines” [
      • Sabaratnam R.
      • Wojtaszewski J.F.P.
      • Højlund K.
      Factors mediating exercise-induced organ crosstalk.
      ,
      • Chow L.S.
      • Gerszten R.E.
      • Taylor J.M.
      • Pedersen B.K.
      • van Praag H.
      • Trappe S.
      • et al.
      Exerkines in health, resilience and disease.
      ]. In particular, myokines are cytokines, small proteins (5–20 KDa), or other proteoglycan peptides that are synthesized, expressed and released by muscle fibers (among other organs) in response to contraction and exert local autocrine and paracrine effects, and distal endocrine effects on a number of organs, including the heart [
      • Severinsen M.C.K.
      • Pedersen B.K.
      Muscle–organ crosstalk: the emerging roles of myokines.
      ]. We discuss the potential roles of dysregulated myokine secretion in patients with HF and skeletal myopathy, paying special attention to its effects not only on skeletal muscle, but also on the heart. On the other hand, we discuss how personalized exercise training may improve exercise capacity and other clinical aspects in HF patients, with myokine regulation being one of the pathophysiological mechanisms involved in the beneficial effects of exercise.

      2. Skeletal myopathy in heart failure

      2.1 General aspects

      At the tissue and biochemical level skeletal myopathy in HF is characterized by major structural and metabolic alterations: the former can include loss of skeletal muscle bulk due to the reduced number and/or size of myocytes, shifts in fiber type with an increase in easily fatigable type IIb fibers, and capillary rarefaction, inflammation and fibrosis; the latter are characterized by a decrease in the effective mitochondria number and/or function, concomitant with a decrease in oxidative capacity and protein synthesis, and an increase in proteolysis, as well as with changes in fatty acid and glucose oxidation [
      • Nijholt K.T.
      • Sánchez-Aguilera P.I.
      • Voorrips S.N.
      • Boer R.A.
      • Westenbrink B.D.
      Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?.
      ,
      • Tucker W.J.
      • Haykowsky M.J.
      • Seo Y.
      • Stehling E.
      • Forman D.E.
      Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function.
      ]. Interestingly, initial evidence from independent studies indicated that some, but not all, skeletal muscle alterations are similar between HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF) when compared with healthy controls [
      • Tucker W.J.
      • Haykowsky M.J.
      • Seo Y.
      • Stehling E.
      • Forman D.E.
      Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function.
      ]. However, Seiler et al. [
      • Seiler M.
      • Bowen T.S.
      • Rolim N.
      • Dieterlen M.-T.
      • Werner S.
      • Hoshi T.
      • et al.
      Skeletal muscle alterations are exacerbated in heart failure with reduced compared with preserved ejection fraction.
      ] recently reported that molecular and cellular skeletal muscle alterations are exacerbated in HFrEF patients compared to HFpEF patients.

      2.2 Major causes

      Traditionally, the origin of the alterations of skeletal muscle in HF was linked to two major mechanisms: hemodynamic and metabolic alterations (Fig. 1).
      Fig. 1
      Fig. 1Pathophysiological approach to the major mechanisms and consequences of skeletal myopathy in heart failure.
      Blood flow and oxygen (O2) delivery to working muscles is reduced in HF, partly due to decreased cardiac output and partly to vasoconstriction of the small muscular arteries secondary to neurohumoral-mediated systemic endothelial dysfunction that accompanies HF [
      • Tucker W.J.
      • Haykowsky M.J.
      • Seo Y.
      • Stehling E.
      • Forman D.E.
      Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function.
      ,
      • Seiler M.
      • Bowen T.S.
      • Rolim N.
      • Dieterlen M.-T.
      • Werner S.
      • Hoshi T.
      • et al.
      Skeletal muscle alterations are exacerbated in heart failure with reduced compared with preserved ejection fraction.
      ]. Although O2 extraction can be increased to account for reduced O2 delivery, skeletal muscle maladaptation in HF may blunt diffusive O2 transport, effectively negating this compensatory response [
      • Esposito F.
      • Mathieu-Costello O.
      • Shabetai R.
      • Wagner P.D.
      • Richardson R.S.
      Limited maximal exercise capacity in patients with chronic heart failure: partitioning the contributors.
      ]. In this regard, skeletal muscle interstitial inflammation and subsequent fibrosis, as well as intermuscular infiltration of adipose tissue (in patients with obesity), lead to significant limitations in O2 diffusion and extraction [
      • Tucker W.J.
      • Haykowsky M.J.
      • Seo Y.
      • Stehling E.
      • Forman D.E.
      Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function.
      ,
      • Lavine K.J.
      • Sierra O.L.
      Skeletal muscle inflammation and atrophy in heart failure.
      ,
      • Dhakal B.P.
      • Malhotra R.
      • Murphy R.M.
      • Pappagianopoulos P.P.
      • Baggish A.L.
      • Weiner R.B.
      • et al.
      Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction.
      ].
      HF is generally associated with systemically increased catabolism and decreased anabolism. For example, an increase in blood levels of catabolic hormones (e.g., cortisol) and a decrease in anabolic hormones (e.g., testosterone and insulin-like growth factor-1) are closely associated with progressive muscle wasting and cachexia, myopathy severity, and poor prognosis in HF [
      • Takada S.
      • Sabe H.
      • Kinugawa S.
      Abnormalities of skeletal muscle, adipocyte tissue, and lipid metabolism in heart failure: practical therapeutic targets.
      ].

      2.3 Main consequences

      Recent evidence suggests that, beyond its contribution to exercise intolerance in patients with HF, the skeletal muscle may also contribute to the pathophysiology of HF at two additional levels: alterations in the metaboreflex and alterations in the secretion of myokines (Fig. 1).
      Patients with HF and skeletal muscle alterations show early accumulation of lactic acid during effort and a less efficient use of high-energy compounds [
      • Tucker W.J.
      • Haykowsky M.J.
      • Seo Y.
      • Stehling E.
      • Forman D.E.
      Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function.
      ]. These disturbances, in turn, trigger exaggerated metaboreflex activation with subsequent sympathetic overactivation and hemodynamic dysregulation characterized by an increase of systemic vascular resistance due to exaggerated peripheral vasoconstriction. Importantly, cardiac output is not increased due to the inability to enhance inotrophy [
      • Crisafulli A.
      • Salis E.
      • Tocco F.
      • Melis F.
      • Milia R.
      • Pittau G.
      • et al.
      Impaired central hemodynamic response and exaggerated vasoconstriction during muscle metaboreflex activation in heart failure patients.
      ]. Thus, it has been proposed that skeletal myopathy contributes to neurohumoral activation and impairment of systemic hemodynamics in HF through a hyperactivated metaboreflex [
      • Piepoli M.F.
      • Crisafulli A.
      Pathophysiology of human heart failure: importance of skeletal muscle myopathy and reflexes.
      ].
      The concept of skeletal muscle as a secretory organ, developed over the last two decades, partly explains how crosstalk between skeletal muscle and distant tissues occurs, and how the beneficial effects of exercise transcend the simple improved skeletal muscle functionality, to encompass systemic responses in distal organs such as the heart, kidney, brain, adipose tissue and liver [
      • Fiuza-Luces C.
      • Santos-Lozano A.
      • Joyner M.
      • Carrera-Bastos P.
      • Picazo O.
      • Zugaza J.L.
      • et al.
      Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors.
      ]. There is now a wealth of data on the synthesis, kinetics of release and biological roles of myokines as mediators of muscle-organ crosstalk [
      • Severinsen M.C.K.
      • Pedersen B.K.
      Muscle–organ crosstalk: the emerging roles of myokines.
      ]. In fact, a recent secretome analysis of human muscle cells identified several hundred nonredundant secreted molecules, of which >300 were classified as potential myokines. Evidence accumulated in recent years suggests that circulating and tissue myokines in HF are associated with exercise tolerance, cardiac abnormalities and outcomes, and systemic effects at different levels [
      • Berezin A.E.
      • Berezin A.A.
      • Lichtenauer M.
      Myokines and heart failure: challenging role in adverse cardiac remodeling, myopathy, and clinical outcomes.
      ]. Therefore, it has been hypothesized that myokine dysregulation might be part of skeletal myopathy in patients with HF and they emerge as potential diagnostic tools and therapeutic targets in this patient population (Graphical Abstract) [
      • Latasa Amézqueta I.
      • Ramírez-Vélez R.
      • Izquierdo M.
      • Díez J.
      Heart failure-related skeletal myopathy. Potential involvement of myokines.
      ].

      3. Myokines in heart failure

      3.1 Dysregulation of myokines in HF

      Pioneering observations early in this century suggesting that interleukin-6 (IL-6) [
      • Steensberg A.
      • van Hall G.
      • Osada T.
      • Sacchetti M.
      • Saltin B.
      • Klarlund Pedersen B.
      Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6.
      ] and tumor necrosis factor-α (TNF-α) [
      • Steensberg A.
      • Keller C.
      • Starkie R.L.
      • Osada T.
      • Febbraio M.A.
      • Pedersen B.K.
      IL-6 and TNF-alpha expression in, release from, contracting human skeletal muscle.
      ] behave as myokines have been confirmed in later studies [
      • Peake J.M.
      • Della Gatta P.
      • Suzuki K.
      • Nieman D.C.
      Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects.
      ]. Thus, the notion that skeletal muscle itself may be a source of molecules recognized to play a role in the pathophysiology of HF [
      • Li H.
      • Chen C.
      • Wang D.W.
      Inflammatory cytokines, immune cells, and organ interactions in heart failure.
      ], provided novel insight on the pathogenic contribution of skeletal myopathy to the systemic maladaptations that characterize HF.
      Experimental and clinical studies carried out in the following 15 years have shown that the regulation of other myokines is also impaired in HF; while some of them are upregulated (e.g., myostatin, IL-6, IL-8, osteonectin, growth differentiation factor-11 [GDF-11], follistatin-related protein 1 [FSTL1]), other are downregulated (e.g., irisin, IL-15, brain-derived neurotrophic factor [BDNF], decorin, myonectin and fibroblast growth factor-21 [FGF-21]) (reviewed in 21). Myokine profiles are variably associated with the severity of skeletal myopathy, adverse cardiac remodelling, and poor clinical outcomes [
      • Berezin A.E.
      • Berezin A.A.
      • Lichtenauer M.
      Myokines and heart failure: challenging role in adverse cardiac remodeling, myopathy, and clinical outcomes.
      ]. In addition, the effects of myokines, either detrimental or beneficial, may be molecule-dependent [
      • Berezin A.E.
      • Berezin A.A.
      • Lichtenauer M.
      Myokines and heart failure: challenging role in adverse cardiac remodeling, myopathy, and clinical outcomes.
      ]. As an illustrative example, a more detailed discussion of available data on myostatin and irisin in HF may cast some light on the potential roles of myokines in this condition.
      Myostatin (also called growth differentiation factor-8) is a cytokine belonging to the transforming growth factor-β (TGF-β) superfamily [
      • McPherron A.C.
      • Lawler A.M.
      • Lee S.J.
      Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member.
      ]. Myostatin is a negative regulator of muscle mass, inhibiting muscle synthesis and augmenting muscle catabolism [
      • Omosule C.L.
      • Phillips C.L.
      Deciphering myostatin's regulatory, metabolic, and developmental influence in skeletal diseases.
      ]. The activation of myostatin triggers the transcription of catabolic target genes, impairs the activation of satellite cells and myogenic factors, and stimulates the ubiquitin–proteasome system. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in the heart [
      • McKoy G.
      • Bicknell K.A.
      • Patel K.
      • Brooks G.
      Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation.
      ]. Myostatin gene and protein expression in skeletal muscle biopsies is higher in patients with HFrEF than in healthy controls [
      • Lenk K.
      • Erbs S.
      • Höllriegel R.
      • Beck E.
      • Linke A.
      • Gielen S.
      • et al.
      Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure.
      ,
      • Bekfani T.
      • Bekhite Elsaied M.
      • Derlien S.
      • Nisser J.
      • Westermann M.
      • Nietzsche S.
      • et al.
      Skeletal muscle function, structure, and metabolism in patients with heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.
      ], and higher in patients with HFpEF than in patients with HFrEF (Fig. 2) [
      • Bekfani T.
      • Bekhite Elsaied M.
      • Derlien S.
      • Nisser J.
      • Westermann M.
      • Nietzsche S.
      • et al.
      Skeletal muscle function, structure, and metabolism in patients with heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.
      ]. Moreover, the expression of myostatin [
      • Castillero E.
      • Ali Z.A.
      • Akashi H.
      • Giangreco N.
      • Wang C.
      • Stöhr E.J.
      • et al.
      Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery.
      ,
      • George I.
      • Bish L.T.
      • Kamalakkannan G.
      • Petrilli C.M.
      • Oz M.C.
      • Naka Y.
      • et al.
      Myostatin activation in patients with advanced heart failure and after mechanical unloading.
      ] and that of its receptor ActRIIB [
      • George I.
      • Bish L.T.
      • Kamalakkannan G.
      • Petrilli C.M.
      • Oz M.C.
      • Naka Y.
      • et al.
      Myostatin activation in patients with advanced heart failure and after mechanical unloading.
      ] in left ventricular (LV) samples was higher in patients with advanced HF than in healthy subjects, although no correlations were found between myocardial myostatin and clinical parameters. Genetic elimination of myostatin [
      • Lim S.
      • McMahon C.D.
      • Matthews K.G.
      • Devlin G.P.
      • Elston M.S.
      • Conaglen J.V.
      Absence of myostatin improves cardiac function following myocardial infarction.
      ] or blockade of the myostatin receptor [
      • Magga J.
      • Vainio L.
      • Kilpiö T.
      • Hulmi J.J.
      • Taponen S.
      • Lin R.
      • et al.
      Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury.
      ] diminishes cardiomyoyte death and myocardial interstitial fibrosis, preserves LV function and increases survival in mice with HF, whereas overexpression of myostatin in cardiomyocytes induces the opposite effects [
      • Biesemann N.
      • Mendler L.
      • Kostin S.
      • Wietelmann A.
      • Borchardt T.
      • Braun T.
      Myostatin induces interstitial fibrosis in the heart via TAK1 and p38.
      ]. There is also evidence that myocardial myostatin is increased in the failing mouse heart and that it is secreted into the circulation, where it can exerts systemic effects including inhibition of skeletal muscle growth [
      • Heineke J.
      • Auger-Messier M.
      • Xu J.
      • Sargent M.
      • York A.
      • Welle S.
      • et al.
      Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure.
      ].
      Fig. 2
      Fig. 2Upper panels. Myostatin mRNA (left panel) and protein (right panel) expression quantified in the vastus lateralis muscle from patients with heart failure with reduced ejection fraction and age-matched healthy controls (Adapted from 31). Lower panels. Expression of the fibronectin type III domain containing 5 (FNDC5) gene encoding for irisin in the vastus lateralis muscle of patients with heart failure with reduced ejection fraction and low or high aerobic performance assessed using oxygen consumption (low or high peak VO2 [≤14 or >14 mL O2·kg−1·min−1, respectively] and low or high ventilatory efficiency [VE/VCO2 slope ≥34 or <34, respectively]) (Adapted from 41).
      On the other hand, exercise induces the muscle expression of the transcriptional coactivator peroxisome proliferator-activated receptor γ co-activator 1 α (PGC-1α), which in turn stimulates the expression of the transmembrane glycoprotein fibronectin type III domain-containing 5 (FNDC5) [
      • Boström P.
      • Wu J.
      • Jedrychowski M.P.
      • Korde A.
      • Ye L.
      • Lo J.C.
      • et al.
      A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.
      ]. Irisin is a proteolytic product of FNDC5, and is secreted by skeletal muscle in response to exercise. Irisin plays an important role in fat metabolism and has been shown to induce the trans-differentiation of white adipose tissue into brown adipose tissue (termed browning), which increases energy expenditure and improves insulin resistance [
      • Boström P.
      • Wu J.
      • Jedrychowski M.P.
      • Korde A.
      • Ye L.
      • Lo J.C.
      • et al.
      A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.
      ,
      • Maak S.
      • Norheim F.
      • Drevon C.A.
      • Erickson H.P.
      Progress and challenges in the biology of FNDC5 and irisin.
      ]. Interestingly, patients with HFrEF with a low aerobic performance (peak VO2 ≤ 14 mL/kg/min and VE/VCO2 slope ≥ 34) exhibit a reduced FNDC5 and PGC-1α expression in skeletal muscle compared with patients with a high aerobic performance (Fig. 2) [
      • Lecker S.H.
      • Zavin A.
      • Cao P.
      • Arena R.
      • Allsup K.
      • Daniels K.M.
      • et al.
      Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure.
      ]. These clinical findings are supported by experimental data showing abnormally reduced FNDC5 and PGC-1α expression in skeletal muscle from rats with HFrEF secondary to ischemic cardiomyopathy [
      • Matsuo Y.
      • Gleitsmann K.
      • Mangner N.
      • Werner S.
      • Fischer T.
      • Bowen T.S.
      • et al.
      Fibronectin type III domain containing 5 expression in skeletal muscle in chronic heart failure-relevance of inflammatory cytokines.
      ]. Irisin can also be produced by the heart [
      • Gür F.
      • Timurkaan S.
      • Yalcin M.
      • Girgin A.
      • Gençer Tarakçı B.
      Immunohistochemical localization of irisin in mole rats (Spalax leucodon).
      ]. Compared with wild-type animals, Fndc5 gene deletion resulted in exacerbation of LV hypertrophy, dysfunction and fibrosis, whereas Fndc5 gene overexpression resulted in attenuation of these phenotypes [
      • Li R.L.
      • Wu S.S.
      • Wu Y.
      • Wang X.X.
      • Chen H.Y.
      • Xin J.J.
      • et al.
      Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway.
      ]. In addition, administration of exogenous irisin mitigated LV hypertrophy, dysfunction and fibrosis in diabetic rodents when compared with non-treated animals [
      • Liu X.
      • Mujahid H.
      • Rong B.
      • Lu Q.-H.
      • Zhang W.
      • Li P.
      • et al.
      Irisin inhibits high glucose-induced endothelial-to-mesenchymal transition and exerts a dose-dependent bidirectional effect on diabetic cardiomyopathy.
      ,
      • Wang J.
      • Zhao Y.T.
      • Zhang L.
      • Dubielecka P.M.
      • Zhuang S.
      • Qin G.
      • et al.
      Irisin improves myocardial performance and attenuates insulin resistance in spontaneous mutation (Leprdb) mice.
      ]. Administration of irisin also improved LV function, decreased cardiomyocyte apoptosis, and protected mitochondria in rats submitted to cardiac ischemia and reperfusion [
      • Wang Z.
      • Chen K.
      • Han Y.
      • Zhu H.
      • Zhou X.
      • Tan T.
      • et al.
      Irisin protects heart against ischemia-reperfusion injury through a SOD2-dependent mitochondria mechanism.
      ].
      As the field of the “myokinome” expands, studies performed in the last years have found that some molecules already known from a long-time or others recently identified also behave also as myokines and may be potentially involved in the pathophysiology of skeletal myopathy, cardiac remodelling and the progression of comorbidities that characterize HF. This is the case for apelin, musclin and several non-coding RNAs. Apelin is a peptide hormone that by activating its G-protein coupled receptor (ApelinR) exerts many biological functions and whose production is induced by muscle contraction [
      • Vinel C.
      • Lukjanenko L.
      • Batut A.
      • Deleruyelle S.
      • Pradère J.-P.
      • Le Gonidec S.
      • et al.
      The exerkine apelin reverses age-associated sarcopenia.
      ]. A number of studies have demonstrated that apelin improves skeletal muscle mass and function, exerts cardioprotective effects and promotes energy expenditure [
      • de Oliveira A.A.
      • Vergara A.
      • Wang X.
      • Vederas J.C.
      • Oudit G.Y.
      Apelin pathway in cardiovascular, kidney, and metabolic diseases: therapeutic role of apelin analogs and apelin receptor agonists.
      ]. In the ventricular tissue of patients with advanced HFrEF, increased [
      • Földes G.
      • Horkay F.
      • Szokodi I.
      • Vuolteenaho O.
      • Ilves M.
      • Lindstedt K.A.
      • et al.
      Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure.
      ] or unchanged apelin levels have been reported [
      • Pitkin S.L.
      • Maguire J.J.
      • Kuc R.E.
      • Davenport A.P.
      Modulation of the apelin/APJ system in heart failure and atherosclerosis in man.
      ], while ApelinR levels are consistently decreased [
      • Földes G.
      • Horkay F.
      • Szokodi I.
      • Vuolteenaho O.
      • Ilves M.
      • Lindstedt K.A.
      • et al.
      Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure.
      ,
      • Pitkin S.L.
      • Maguire J.J.
      • Kuc R.E.
      • Davenport A.P.
      Modulation of the apelin/APJ system in heart failure and atherosclerosis in man.
      ]. Reduced skeletal muscle musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload [
      • Szaroszyk M.
      • Kattih B.
      • Martin-Garrido A.
      • Trogisch F.A.
      • Dittrich G.M.
      • Grundi A.
      • et al.
      Skeletal muscle derived musclin protects the heart during pathological overload.
      ]. Mechanistically, musclin enhances the abundance of C-type natriuretic peptide, thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling [
      • Szaroszyk M.
      • Kattih B.
      • Martin-Garrido A.
      • Trogisch F.A.
      • Dittrich G.M.
      • Grundi A.
      • et al.
      Skeletal muscle derived musclin protects the heart during pathological overload.
      ]. Of interest, reduced expression of OSTN, which encodes musclin, has been found in skeletal muscle of HF mice and HF patients [
      • Szaroszyk M.
      • Kattih B.
      • Martin-Garrido A.
      • Trogisch F.A.
      • Dittrich G.M.
      • Grundi A.
      • et al.
      Skeletal muscle derived musclin protects the heart during pathological overload.
      ]. On the other hand, the relevance of non-coding RNAs in muscle biology is evidenced by studies demonstrating that microRNA and long non-coding RNA profiles are dysregulated in a number of conditions associated with impaired exercise capacity [
      • Gomes C.P.C.
      • de Gonzalo-Calvo D.
      • Toro R.
      • Fernandes T.
      • Theisen D.
      • Wang D.Z.
      • et al.
      Non-coding RNAs and exercise: pathophysiological role and clinical application in the cardiovascular system.
      ,
      • Bonilauri B.
      • Dallagiovanna B.
      Long non-coding RNAs are differentially expressed after different exercise training programs.
      ]. Both microRNAs and long non-coding RNAs are sensitive to muscle contraction in response to different protocols of exercise training both in humans and animal models, which points to their potential role in the exercise-induced adaptations of skeletal muscle [
      • Gomes C.P.C.
      • de Gonzalo-Calvo D.
      • Toro R.
      • Fernandes T.
      • Theisen D.
      • Wang D.Z.
      • et al.
      Non-coding RNAs and exercise: pathophysiological role and clinical application in the cardiovascular system.
      ,
      • Bonilauri B.
      • Dallagiovanna B.
      Long non-coding RNAs are differentially expressed after different exercise training programs.
      ]. In addition, experimental data suggest that some non-coding RNAs produced in response to exercise exert direct effects on the heart. For instance, whereas microRNA-1192 protects cardiomyocytes from hypoxia via targeting caspase 3 [
      • Wang Y.
      • Tian M.-M.
      • Mi C.-J.
      • Chen K.-L.
      • Ji Y.-C.
      • Wang L.
      • et al.
      Exercise protects the heart against myocardial infarction through upregulation of miR-1192.
      ], it appears that the long non-coding ExACT1 facilitates pathological LV hypertrophy [
      • Li H.
      • Trager L.E.
      • Liu X.
      • Hastings M.H.
      • Xiao C.
      • Guerra J.
      • et al.
      lncExACT1 and DCHS2 regulate physiological and pathological cardiac growth.
      ].
      In summary, from a mechanistic point of view the hypothesis emerges that myokine dysregulation may be involved in the impairment of skeletal muscle, heart and other organs in the context of HF (Graphical Abstract). However, more thorough studies, both at the cellular and pre-clinical levels, are needed to fully resolve the controversies of their exact contribution to skeletal myopathy, adverse cardiac remodelling and comorbidities in HF.

      3.2 Myokines as biomarkers in HF

      Taking into account that myokines are secreted and reach the blood stream, their potential clinical usefulness as biomarkers in HF has being suggested (Fig. 2) [
      • Duan J.
      • Zhu B.
      • Wu Y.
      • Chen Z.
      • Yang L.
      Myokines: an available biomarker to evaluate cardiac function?.
      ]. Indeed, supporting this notion, a study performed in a large, heterogeneous cohort of 2329 patients with HF showed that circulating IL-6 is abnormally elevated in these patients and is associated with cardiac dysfunction severity and poor clinical outcomes [
      • Markousis-Mavrogenis G.
      • Tromp J.
      • Ouwerkerk W.
      • Devalaraja M.
      • Anker S.D.
      • Cleland J.G.
      • et al.
      The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study.
      ]. The prognostic value of elevated circulating IL-6 levels in HF was corroborated in a meta-analysis including 28 studies [
      • Liu M.
      • Chen J.
      • Huang D.
      • Ke J.
      • Wu W.
      A meta-analysis of proinflammatory cytokines in chronic heart failure.
      ]. Similarly, increased levels of serum TNF-α were found in patients with severe HF presenting with cachexia, advanced adverse cardiac remodelling and pronounced exercise intolerance [
      • Levine B.
      • Kalman J.
      • Mayer L.
      • Fillit H.M.
      • Packer M.
      Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.
      ,
      • Rauchhaus M.
      • Doehner W.
      • Francis D.P.
      • Davos C.
      • Kemp M.
      • Liebenthal C.
      • et al.
      Plasma cytokine parameters and mortality in patients with chronic heart failure.
      ]. Of interest, since the stability of plasma concentrations of soluble TNF-receptors (sTNFR-1 and -2) is higher than that of TNFα itself, this may be the reason why sTNFR-1 is a better predictor than TNFα in HF patients [
      • Rauchhaus M.
      • Doehner W.
      • Francis D.P.
      • Davos C.
      • Kemp M.
      • Liebenthal C.
      • et al.
      Plasma cytokine parameters and mortality in patients with chronic heart failure.
      ].
      Regarding serum levels of myostatin three studies reported higher concentration in patients with chronic HF than in healthy controls [
      • George I.
      • Bish L.T.
      • Kamalakkannan G.
      • Petrilli C.M.
      • Oz M.C.
      • Naka Y.
      • et al.
      Myostatin activation in patients with advanced heart failure and after mechanical unloading.
      ,
      • Chen P.
      • Liu Z.
      • Luo Y.
      • Chen L.
      • Li S.
      • Pan Y.
      • et al.
      Predictive value of serum myostatin for the severity and clinical outcome of heart failure.
      ,
      • Gruson D.
      • Ahn S.A.
      • Ketelslegers J.M.
      • Rousseau M.F.
      Increased plasma myostatin in heart failure.
      ], while one study reported similar levels [
      • Lenk K.
      • Erbs S.
      • Höllriegel R.
      • Beck E.
      • Linke A.
      • Gielen S.
      • et al.
      Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure.
      ] and another study reported lower levels [
      • Furihata T.
      • Kinugawa S.
      • Fukushima A.
      • Takada S.
      • Homma T.
      • Masaki Y.
      • et al.
      Serum myostatin levels are independently associated with skeletal muscle wasting in patients with heart failure.
      ]. When myostatin was abnormally increased, no differences were reported between patients with HFrEF and HFpEF [
      • Chen P.
      • Liu Z.
      • Luo Y.
      • Chen L.
      • Li S.
      • Pan Y.
      • et al.
      Predictive value of serum myostatin for the severity and clinical outcome of heart failure.
      ], or between patients with ischemic HF or with non-ischemic dilated cardiomyopathy [
      • Gruson D.
      • Ahn S.A.
      • Ketelslegers J.M.
      • Rousseau M.F.
      Increased plasma myostatin in heart failure.
      ]. Whereas some studies reported associations between serum myostatin and severity of HF as assessed by the New York Heart Association Class (NYHA) and the plasma levels of natriuretic peptides [
      • Chen P.
      • Liu Z.
      • Luo Y.
      • Chen L.
      • Li S.
      • Pan Y.
      • et al.
      Predictive value of serum myostatin for the severity and clinical outcome of heart failure.
      ,
      • Gruson D.
      • Ahn S.A.
      • Ketelslegers J.M.
      • Rousseau M.F.
      Increased plasma myostatin in heart failure.
      ], others did not find any association [
      • Lenk K.
      • Erbs S.
      • Höllriegel R.
      • Beck E.
      • Linke A.
      • Gielen S.
      • et al.
      Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure.
      ,
      • George I.
      • Bish L.T.
      • Kamalakkannan G.
      • Petrilli C.M.
      • Oz M.C.
      • Naka Y.
      • et al.
      Myostatin activation in patients with advanced heart failure and after mechanical unloading.
      ,
      • Furihata T.
      • Kinugawa S.
      • Fukushima A.
      • Takada S.
      • Homma T.
      • Masaki Y.
      • et al.
      Serum myostatin levels are independently associated with skeletal muscle wasting in patients with heart failure.
      ]. In an analysis of 288 patients with HFrEF and HFpEF and 62 healthy controls, an independent association was observed between myostatin levels and clinical outcomes, with those patients in the highest tertile of myostatin presenting the highest rates of hospitalization for HF and mortality [
      • Chen P.
      • Liu Z.
      • Luo Y.
      • Chen L.
      • Li S.
      • Pan Y.
      • et al.
      Predictive value of serum myostatin for the severity and clinical outcome of heart failure.
      ]. Myostatin was also an independent predictor of survival in HF patients (Fig. 3) [
      • Chen P.
      • Liu Z.
      • Luo Y.
      • Chen L.
      • Li S.
      • Pan Y.
      • et al.
      Predictive value of serum myostatin for the severity and clinical outcome of heart failure.
      ].
      Fig. 3
      Fig. 3Left panel. Kaplan-Meier estimates of survival in patients with heart failure (HF) according to tertiles of serum myostatin. (Adapted from 62). Right panel. Plasma irisin levels decreased in relation to the severity of sarcopenia (defined according to the SARC-F [S, Strength; A, Assistance in walking; R, Rise from a chair; C, Climb stairs; F, Falls] questionnaire scoring) in HF patients. (Adapted from 66).
      Serum levels of irisin are lower in patients with HFrEF than in healthy volunteers [
      • Abd El-Mottaleb N.A.
      • Galal H.M.
      • El Maghraby K.M.
      • Gadallah A.I.
      Serum irisin level in myocardial infarction patients with or without heart failure.
      ,
      • Qaisar R.
      • Karim A.
      • Muhammad T.
      • Shah I.
      • Khan J.
      Prediction of sarcopenia using a battery of circulating biomarkers.
      ], lower in patients with HFrEF than in those with HFpEF [
      • Silvestrini A.
      • Bruno C.
      • Vergani E.
      • Venuti A.
      • Favuzzi A.M.R.
      • Guidi F.
      • et al.
      Circulating irisin levels in heart failure with preserved or reduced ejection fraction: a pilot study.
      ], and lower in patients with HF and cachexia than in those without cachexia [
      • Sobieszek G.
      • Powrózek T.
      • Mazurek M.
      • Skwarek-Dziekanowska A.
      • Małecka-Massalska T.
      Electrical and hormonal biomarkers in cachectic elderly women with chronic heart failure.
      ]. Correlation analyses in patients with HF showed that serum levels of irisin correlate directly with LV ejection fraction [
      • Abd El-Mottaleb N.A.
      • Galal H.M.
      • El Maghraby K.M.
      • Gadallah A.I.
      Serum irisin level in myocardial infarction patients with or without heart failure.
      ,
      • Kalkan A.K.
      • Cakmak H.A.
      • Erturk M.
      • Kalkan K.E.
      • Uzun F.
      • Tasbulak O.
      • et al.
      Adropin and irisin in patients with cardiac cachexia.
      ], and inversely with NYHA class [
      • Sobieszek G.
      • Powrózek T.
      • Mazurek M.
      • Skwarek-Dziekanowska A.
      • Małecka-Massalska T.
      Electrical and hormonal biomarkers in cachectic elderly women with chronic heart failure.
      ], natriuretic peptide levels [
      • Sobieszek G.
      • Powrózek T.
      • Mazurek M.
      • Skwarek-Dziekanowska A.
      • Małecka-Massalska T.
      Electrical and hormonal biomarkers in cachectic elderly women with chronic heart failure.
      ,
      • Kalkan A.K.
      • Cakmak H.A.
      • Erturk M.
      • Kalkan K.E.
      • Uzun F.
      • Tasbulak O.
      • et al.
      Adropin and irisin in patients with cardiac cachexia.
      ], and LV dimensions [
      • Qaisar R.
      • Karim A.
      • Muhammad T.
      • Shah I.
      • Khan J.
      Prediction of sarcopenia using a battery of circulating biomarkers.
      ]. Notably, the levels of circulating irisin were negatively associated with the severity of sarcopenia in HF patients (Fig. 3) [
      • Qaisar R.
      • Karim A.
      • Muhammad T.
      • Shah I.
      • Khan J.
      Prediction of sarcopenia using a battery of circulating biomarkers.
      ].
      Altogether, cumulative evidence indicates that circulating levels of myokines are altered in HF and associated with features of adverse cardiac remodelling and with poor cardiac prognosis, thus reinforcing the role of skeletal myopathy in HF evolution and prognosis (Graphical abstract). Nevertheless, it is still unclear how strongly related are changes in peripheral blood concentrations of myokines in HF with skeletal myopathy since, despite their primary skeletal origin, other tissues are capable of producing and releasing them. In addition, there is limited robust evidence on the independent predictive value of myokine signatures and their added value on top of traditional circulating cardiac biomarkers.

      4. Exercise in patients with heart failure

      4.1 General aspects

      Exercise intolerance is preceded by an accelerated decline in functional capacity, measured objectively as peak VO2, and manifests clinically as fatigue, dyspnea, and reduced QoL [
      • Cattadori G.
      • Segurini C.
      • Picozzi A.
      • Padeletti L.
      • Anzà C.
      Exercise and heart failure: an update.
      ]. Therefore, exercise is recommended (class 1, level A) for all patients who are able in order to improve exercise capacity, QoL, and reduce HF hospitalizations [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ,
      • Heidenreich P.A.
      • Bozkurt B.
      • Aguilar D.
      • Allen L.A.
      • Byun J.J.
      • Colvin M.M.
      • et al.
      2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      ]. A supervised, exercise-based, cardiac rehabilitation programme should be also considered (class 2b, level c [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ] or class 2b, level b-nr [
      • Heidenreich P.A.
      • Bozkurt B.
      • Aguilar D.
      • Allen L.A.
      • Byun J.J.
      • Colvin M.M.
      • et al.
      2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      ]) in patients with more severe disease, frailty, or with comorbidities.
      To advance HF therapy in terms of improving clinical outcomes, muscle strength, functional capacity and QoL, implementing novel strategies based on emerging knowledge and person-centered therapy, including individualized and tailored telemedicine and technology-based programs seems necessary [
      • Izquierdo M.
      • Merchant R.A.
      • Morley J.E.
      • Anker S.D.
      • Aprahamian I.
      • Arai H.
      • et al.
      International exercise recommendations in older adults (ICFSR): expert consensus guidelines.
      ,
      • Izquierdo M.
      • Duque G.
      • Morley J.E.
      Physical activity guidelines for older people: knowledge gaps and future directions.
      ]. In this conceptual framework myokines may add a new dimension to the design of personalized exercise training in HF patients (Graphical Abstract).

      4.2 Effects of exercise on myokines in HF

      Preliminary studies in patients with cardiovascular conditions, including HF, show that physical training-induced myokine changes are associated with improvement in exercise tolerance and cardiovascular function [
      • Barbalho S.M.
      • Flato U.A.P.
      • Tofano R.J.
      • Goulart R.A.
      • Guiguer E.L.
      • Detregiachi C.R.P.
      • et al.
      Physical exercise and myokines: relationships with sarcopenia and cardiovascular complications.
      ]. Exercise-derived myokines might be involved in the beneficial effects of exercise in HF through three main types of effects: 1) promoting a systemic anabolic milieu with improvement of skeletal myopathy; 2) affording direct cardiac protection; and 3) ameliorating disturbances of energy metabolism. For instance, whereas the anabolic myokine IGF-1 decreases [
      • Hambrecht R.
      • Schulze P.C.
      • Gielen S.
      • Linke A.
      • Möbius-Winkler S.
      • Yu J.
      • et al.
      Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure.
      ] and the catabolic myokine TNF-α increases [
      • Gielen S.
      • Adams V.
      • Möbius-Winkler S.
      • Linke A.
      • Erbs S.
      • Yu J.
      • et al.
      Anti-inflammatory effects of exercise train-ing in the skeletal muscle of patients with chronic heart failure.
      ] in the skeletal muscle of HF patients, skeletal muscle IGF-1 increases [
      • Tzanis G.
      • Philippou A.
      • Karatzanos E.
      • Dimopoulos S.
      • Kaldara E.
      • Nana E.
      • et al.
      Effects of high-intensity interval exercise training on skeletal myopathy of chronic heart failure.
      ] and skeletal muscle TNF-α decreases [
      • Gielen S.
      • Adams V.
      • Möbius-Winkler S.
      • Linke A.
      • Erbs S.
      • Yu J.
      • et al.
      Anti-inflammatory effects of exercise train-ing in the skeletal muscle of patients with chronic heart failure.
      ] with endurance exercise. High-intensity interval exercise training improved skeletal myopathy in patients with chronic heart failure, and these effects were associated with increased production of members of member of the IGF-1 family and of IGFBP-3 [
      • Piccirillo R.
      Exercise-induced myokines with therapeutic potential for muscle wasting.
      ]. Direct cardioprotection can be induced by a single bout of exercise and can be maintained for months with regular exercise; the mechanisms reportedly involved include increased cardiac storage of nitric oxide and decreased oxidative stress with resulting improvement of endothelial function, activation of pro-survival kinases of the reperfusion injury salvage kinase (RISK) pathway, and improved calcium-retaining capacity of mitochondria [
      • Fiuza-Luces C.
      • Santos-Lozano A.
      • Joyner M.
      • Carrera-Bastos P.
      • Picazo O.
      • Zugaza J.L.
      • et al.
      Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors.
      ]. Irisin [
      • Ma J.
      • Chen K.
      The role of irisin in multiorgan protection.
      ], apelin [
      • Pitkin S.L.
      • Maguire J.J.
      • Kuc R.E.
      • Davenport A.P.
      Modulation of the apelin/APJ system in heart failure and atherosclerosis in man.
      ] and FSTL1 [
      • Ogura Y.
      • Ouchi N.
      • Ohashi K.
      • Shibata R.
      • Kataoka Y.
      • Kambara T.
      • et al.
      Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models.
      ] appear to be the myokines more involved in these cardioprotective effects. In addition, myokines mediate exercise-stimulated muscle lipid oxidation and oxidative metabolism in an autocrine fashion (e.g., IL-15 and BDNF), exercise-induced hepatic neoglucogenesis and fatty acids uptake (e.g., myonectin) and white adipose tissue lipolysis and brown adipose tissue thermogenesis (e.g., irisin and FGF-21) through endocrine communication [
      • Sabaratnam R.
      • Wojtaszewski J.F.P.
      • Højlund K.
      Factors mediating exercise-induced organ crosstalk.
      ,
      • Laurens C.
      • Bergouignan A.
      • Moro C.
      Exercise-released myokines in the control of energy metabolism.
      ].
      The regulation of myokines through exercise can be differential and is more or less specific depending on the type of exercise. For instance, myostatin is primarily inhibited by concurrent training [
      • Bagheri R.
      • Moghadamb B.H.
      • Church D.D.
      • Tinsleyd G.M.
      • Eskandari M.
      • Hooshmand Moghadam B.H.
      • et al.
      The effects of concurrent training order on body composition and serum concentrations of follistatin, myostatin and GDF11 in sarcopenic elderly men.
      ], whereas irisin is mostly induced by resistance exercises as well as by heavy strength training [
      • Nygaard H.
      • Slettalokken G.
      • Vegge G.
      • Hollan I.
      • Whist J.E.
      • Strand T.
      • et al.
      Irisin in blood increases transiently after single sessions of intense endurance exercise and heavy strength training.
      ], On the other hand, apelin is stimulated by endurance training [
      • Földes G.
      • Horkay F.
      • Szokodi I.
      • Vuolteenaho O.
      • Ilves M.
      • Lindstedt K.A.
      • et al.
      Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure.
      ]. Some experimental and clinical observations support that these aspects may be relevant for the prescription of physical exercise in HF.
      It has been reported that, in patients with HFrEF 12-weeks of concurrent training led to reductions in skeletal muscle myostatin mRNA and protein with final values significantly lower than in the group of HF patients that continued their sedentary style of life [
      • Lenk K.
      • Erbs S.
      • Höllriegel R.
      • Beck E.
      • Linke A.
      • Gielen S.
      • et al.
      Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure.
      ]. These findings have been corroborated in a rat model of HF [
      • Lenk K.
      • Schur R.
      • Linke A.
      • Erbs S.
      • Matsumoto Y.
      • Adams V.
      • et al.
      Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model.
      ]. Although there are no published data on the effect of physical training on circulating myostatin levels, in the only published study showing lower levels in HF patients compared to controls most of patients were following an exercise training program when they were tested but none of the controls did [
      • Chen P.
      • Liu Z.
      • Luo Y.
      • Chen L.
      • Li S.
      • Pan Y.
      • et al.
      Predictive value of serum myostatin for the severity and clinical outcome of heart failure.
      ].
      While no data are yet available on the effects of physical training on irisin in HF patients, there is evidence on its effects in patients with overweight or obesity. In fact, Kim et al. [
      • Kim H.-J.
      • Lee H.-J.
      • So B.
      • Son J.S.
      • Yoon D.
      • Song W.
      Effect of aerobic training and resistance training on circulating irisin level and their association with change of body composition in overweight/obese adults: a pilot study.
      ] found that in overweight/obese adults circulating irisin was increased in subjects submitted to resistance training but did not change in subjects submitted to aerobic training. In addition, the authors reported a positive correlation between the change of circulating irisin and muscle mass and a negative correlation with fat mass [
      • Kim H.-J.
      • Lee H.-J.
      • So B.
      • Son J.S.
      • Yoon D.
      • Song W.
      Effect of aerobic training and resistance training on circulating irisin level and their association with change of body composition in overweight/obese adults: a pilot study.
      ]. The potential relevance of these findings in HF is given by several observations: 1) obesity is present in 80 % of patients with HFpEF [
      • Haass M.
      • Kitzman D.W.
      • Anand I.S.
      • Miller A.
      • Zile M.R.
      • Massie B.M.
      • et al.
      Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial.
      ] and frequently acts as a co-incubator for comorbidities such as diabetes mellitus, metabolic syndrome and hypertension [
      • Harada T.
      • Obokata M.
      Obesity-related heart failure with preserved ejection fraction: pathophysiology, diagnosis, and potential therapies.
      ]; 2) sarcopenic obesity, a clinical condition defined by the coexistence of obesity with a decline in muscle mass and related strength and functionality, is consistently reported in HFpEF patients and poses as a major limitation to exercise capacity [
      • Kitzman D.W.
      • Brubaker P.
      • Morgan T.
      • Haykowsky M.
      • Hundley G.
      • Kraus W.E.
      • et al.
      Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial.
      ]; and 3) HFpEF patients with sarcopenic obesity present with severely reduced exercise capacity due to both obesity [
      • Carbone S.
      • Canada J.M.
      • Buckley L.F.
      • Trankle C.R.
      • Dixon D.L.
      • Buzzetti R.
      • et al.
      Obesity contributes to exercise intolerance in heart failure with preserved ejection fraction.
      ] and sarcopenia [
      • Emami A.
      • Saitoh M.
      • Valentova M.
      • Sandek A.
      • Evertz R.
      • Ebner N.
      • et al.
      Comparison of sarcopenia and cachexia in men with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF).
      ].

      5. Roadmap to enhance the potential role of myokines in HF

      Important remaining issues deserve further consideration in order to establish the role of myokines in understanding and prescribing exercise training as a therapy for HF (Table 1). Regarding the robustness of available data some concerns include the lack of consistency between the acute and chronic exercise response, discrepancies between patients and animal models of exercise, and interpretation challenges due to variability in outcomes and sampling, as well in the pre-analytical processing of biomaterials under study. Importantly, we must recognize that the current proposal for a potential role of myokines in HF is based on information provided by a limited number of small clinical trials. Therefore, we make a call to action for designing large trials evaluating the aforementioned approach to assess incremental results.
      Table 1A three-step road map for potentiating the usefulness of myokines in patients with heart failure.
      • 1.
        Deepen in the fundamental knowledge on myokines
      • a.
        Clarify the muscle profile response to different programs of exercise
      • b.
        Characterize their roles in multi-organ cross-talk as part of exerkines
      • c.
        Take advantage of omic technologies to advance in discovery and validation
      • 2.
        Expand and strength the available information on myokines in HF
      • a.
        Perform large clinical studies to collect more data in different HF populations
      • b.
        Optimize the methodology and the processing of samples to measure
      • c.
        Develop studies in animal models mimicking human HF
      • 3.
        Incorporate myokines into novel technological developments for HF
      • a.
        Implement as parameters for remote monitoring in exercising patients
      • b.
        Incorporate as novel oral compounds in non-exercising patients
      • c.
        Standardize as data for reporting and sharing in telemedicine
      HF, means heart failure.
      Despite the acceleration in exerkine-related research since the identification of IL-6 as a myokine in 2000 [
      • Steensberg A.
      • van Hall G.
      • Osada T.
      • Sacchetti M.
      • Saltin B.
      • Klarlund Pedersen B.
      Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6.
      ], much remains to be done in the scientific areas of research, technology and therapeutic interventions. Specifically, a critical need exists to move beyond the ‘skeletal muscle-centric’ view of myokines and focus more on their roles in inter-organ communication, immune regulation, metabolic adaptation, cardiovascular fitness, and overall health in HF patients. The multiple cross-talks between myokines and other non-muscle exerkines is another aspect that needs to be studied in depth to adequately characterize the role of these molecular mediators in the beneficial effects of exercise in HF patients with associated comorbidities.
      It can be expected that through deep omics profiling (transcriptome, proteome and metabolome) of biomaterials (including extracellular vesicles as carriers of molecular signals and drivers of inter-organ crosstalk) from humans and rodents with HF before and after acute exercise as well as chronic exercise training many more myokines and exerkines will be discovered [
      • Whitham M.
      • Febbraio M.A.
      The ever-expanding myokinome: discovery challenges and therapeutic implications.
      ]. In addition to molecular discoveries, substantial clinical work remains to decipher the dosage and type of exercise needed to elicit positive HF outcomes.
      There is a need to develop novel technologies, including wearable technologies and devices, to capture the quantitative and dynamic changes of myokines over variable periods of time under the effects of physical training in patients with HF. In this regard, the establishment of community standards for data reporting and sharing is mandatory to effectively advance the translation of research into therapy.
      Finally, as the role of myokines and other exerkines and their biological effects are increasingly clarified, they may potentially be harnessed to mimic the benefits of exercise in individuals who are limited in their exercise capacity or to counterbalance a metabolic non-response or adverse response to exercise, as it is the case in patients with the diagnosis of advanced HF [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ,
      • Heidenreich P.A.
      • Bozkurt B.
      • Aguilar D.
      • Allen L.A.
      • Byun J.J.
      • Colvin M.M.
      • et al.
      2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      ]. The past decade has witnessed growing scientific and commercial interest in the identification of bioactive oral compounds that mimic or potentiate the effects of exercise, the so-called ‘exercise pills’. These compounds have, to date, typically targeted skeletal muscle in an attempt to stimulate some of the adaptations to exercise induced by endurance training. Accordingly, they fail to impart many of the broad health protecting effects of exercise that are seen in tissues and organs other than skeletal muscle [
      • Hawley J.A.
      • Joyner M.J.
      • Green D.J.
      Mimicking exercise: what matters most and where to next?.
      ]. Therefore, future research in the field must move beyond the current ‘myocentric’ paradigm.

      6. Conclusions

      The preliminary data discussed here suggest that the study of myokines may provide new insights into the pathophysiology of HF-related skeletal myopathy and that they may be explored as potential biomarkers for the phenotyping and prognostic stratification of this condition in patients with HF, particularly in patients with HFpEF and associated metabolic comorbidities who may especially benefit from exercise's ability to induce myokines and other exerkines [
      • Leal L.G.
      • Lopes M.A.
      • Batista M.L.
      Physical exercise-induced myokines and muscle-adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases.
      ]. In addition, it can be hypothesized that myokines might be useful for personalizing the modality and dose of physical exercise to be prescribed in these patients (see Fig. 2).
      Establishing molecular links between skeletal myopathy and improved HF management can only strengthen the implementation of precision medicine-based management of HF. In this context, myokine (and other exerkines)-guided physical exercise might contribute to a better QoL and likely an improved prognosis, and thus contribute to a better health system performance in terms of cost-effectiveness.

      Sources of funding

      Instituto de Salud Carlos III (Spain) ( CB16/11/00483 to JD, PI18/01469 co-financed by “Fondos Europeos de Desarrollo Regional to AG, CP18/0150 Miguel Servet Fellow to AG-H); Ministerio de Ciencia e Innovación (Spain) ( PID2020-113098RB-I00 to MI); European Commission CRUCIAL project (grant agreement 848109 to AG). Open access funding provided by Universidad Pública de Navarra .

      Declaration of competing interest

      The authors have no conflicts of interest to disclose.

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