Curcumin treatment enhances the effect of exercise on mitochondrial biogenesis in skeletal muscle by increasing cAMP levels



      In response to physiologic stressors, skeletal muscle has the potential to elicit wide variety of adaptive responses, such as biogenesis of mitochondria and clearance of damaged mitochondria to promote healthy muscle. The polyphenol curcumin, derived from the rhizome Curcuma longa L., is a natural antioxidant that exhibits various pharmacological activities and therapeutic properties. However, the effect of curcumin on the regulation of mitochondrial biogenesis in skeletal muscle remains unknown. The present study aimed to examine the effects of combination of endurance training (eTR) and curcumin treatment on the expression of AMPK, SIRT1, PGC-1α, and OXPHOS subunits, mitochondrial DNA copy number, and CS activity in rat skeletal muscle. Furthermore, the present study also examined the effect of exercise and curcumin treatment on the levels of cAMP and downstream targets of PKA including phosphorylated CREB and LKB-1.


      Ten-week-old male Wistar rats were randomly divided into non-eTR and eTR groups. Low doses (50 mg/kg-BW/day) or high doses (100 mg/kg-BW/day) of curcumin dissolved in dimethyl sulfoxide (DMSO) were injected intraperitoneally in all animals for 28 days to investigate the effect of curcumin alone and the combined effect of curcumin with eTR. Western blotting (WB) and immunoprecipitation (IP) were performed to detect the presence of proteins.


      Our results demonstrated that combination of curcumin treatment and eTR increased the expression of COX-IV, OXPHOS subunits, mitochondrial DNA copy number and CS activity in the gastrocnemius (Gas) and soleus (Sol) muscles. In addition, this combination increased AMPK phosphorylation, NAD+/NADH ratio, SIRT1 expression, and PGC-1α deacetylation. Furthermore, curcumin treatment as well as exercise also increased levels of cAMP and downstream target of PKA including phosphorylation CREB and LKB-1 which are involved in the regulation of mitochondrial biogenesis.


      Taken together, these results suggest that the combination of curcumin treatment and eTR has the potential to accelerate mitochondrial biogenesis in skeletal muscle by increasing cAMP levels.


      AMPK (5′ adenosine monophosphate-activated protein kinase), BW (body weight), cAMP (cyclic adenosine monophosphate), CREB (cAMP response element binding protein), COX-IV (cytochrome c oxidase subunit IV), CS (citrate synthase), DMSO (dimethyl sulfoxide), DNA (deoxyribonucleic acid), eTR (endurance training), Gas (gastrocnemius muscle), IP (immunoprecipitation), LKB-1 (liver kinase B1), NAD (nicotinamide adenine dinucleotide), NADH (nicotinamide adenine dinucleotide hydrogen), OXPHOS (oxidative phosphorylation), PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1alpha), PKA (protein kinase A), SIRT1 (sirtuin 1), Sol (soleus muscle), WB (western blotting), GLUT4 (Glucose transporter 4), NRF1/2 (nuclear respiratory factor1/2), GA (guanine adenine), Tfam (transcription factor A), mRNA (messenger ribonucleid acid), ADP (adenosine diphosphate), MMP (mitochondrial membrane potential), ATP (adenosine triphosphate), ROS (reactive oxygen species), NOS (nitric oxide synthase)


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