1 Cell Research 2011 Vol: 22(3):551-564. DOI: 10.1038/cr.2011.205

TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice

Impaired aerobic exercise capacity and skeletal muscle dysfunction are associated with cardiometabolic diseases. Acute administration of capsaicin enhances exercise endurance in rodents, but the long-term effect of dietary capsaicin is unknown. The capsaicin receptor, the transient receptor potential vanilloid 1 (TRPV1) cation channel has been detected in skeletal muscle, the role of which remains unclear. Here we report the function of TRPV1 in cultured C2C12 myocytes and the effect of TRPV1 activation by dietary capsaicin on energy metabolism and exercise endurance of skeletal muscles in mice. In vitro, capsaicin increased cytosolic free calcium and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in C2C12 myotubes through activating TRPV1. In vivo, PGC-1α in skeletal muscle was upregulated by capsaicin-induced TRPV1 activation or genetic overexpression of TRPV1 in mice. TRPV1 activation increased the expression of genes involved in fatty acid oxidation and mitochondrial respiration, promoted mitochondrial biogenesis, increased oxidative fibers, enhanced exercise endurance and prevented high-fat diet-induced metabolic disorders. Importantly, these effects of capsaicin were absent in TRPV1-deficient mice. We conclude that TRPV1 activation by dietary capsaicin improves energy metabolism and exercise endurance by upregulating PGC-1α in skeletal muscles. The present results indicate a novel therapeutic strategy for managing metabolic diseases and improving exercise endurance.

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Figures
Figure 1: TRPV1 characterization in skeletal muscles. (A) Immunoblot of TRPV1 in skeletal muscle (SKM) from wild-type (WT) and TRPV1 knockout (TRPV1−/−) mice and in C2C12 myotubes with or without TRPV1 RNAi (T-RNAi). The arrowhead indicates the band corresponding to TRPV1 protein. (B) TRPV1 localization in C2C12 myotubes and mice myofibers was shown with immunofluorescence. Bar = 50 μm. (C, D) Representative curves (C) and summary data (D) showing capsaicin (100 nM)-induced [Ca2+]i changes in cells with or without T-RNAi and cells pretreated with the specific TRPV1 inhibitor iRTX (1 μM) for 5 min. **P < 0.01 vs control. (E) Immunoblot of TRPV1 in C2C12 myotubes with (Cap) or without (Con) capsaicin (100 nM) treatment for 24 h. *P < 0.05 vs Con. (F) Immunoblot of TRPV1 in skeletal muscles of WT mice with (Cap) or without (Con) 4 months of capsaicin administration. *P < 0.05 vs Con. Summary data are means ± S.E.M. for three to four independent experiments. Figure 2: TRPV1 activation increases PGC-1α expression and mitochondrial biogenesis in a Ca2+-dependent manner. (A) Immunoblot of PGC-1α in C2C12 myotubes treated with capsaicin (100 nM) in the presence or absence of the TRPV1 inhibitor iRTX (1 μM) or the intracellular Ca2+ chelator BAPTA (10 μM). (B, C) Protein expression of genes involved in fatty acid oxidation, glycolysis (B) and mitochondrial respiration (C) in myotubes treated with capsaicin (100 nM) in the presence or absence of iRTX (1 μM). (D, E) Mitochondrial content (D) and ATP production (E) in myotubes. C2C12 cells were treated with capsaicin (100 nM) in the presence or absence of iRTX (1 μM) or BAPTA (10 μM) for 24 h. Data are means ± S.E.M. for three independent experiments. Con, control; Cap, capsaicin. *P < 0.05, **P < 0.01 vs Con. #P < 0.05, ##P < 0.01 vs Cap. Figure 3: Activation of TRPV1 by dietary capsaicin up-regulates PGC-1α and improves mitochondrial function and muscle remodeling. (A-D) Protein expression of genes involved in fatty acid oxidation, glycolysis, fiber specification (A-C) and mitochondrial respiration (D) in skeletal muscles from WT and TRPV1−/− mice fed a regular diet (Con) or a capsaicin diet (Cap). (E) Mitochondrial mass in gastrocnemius muscle shown by transmission electron microscopy. (F) State 3 and state 4 respiration and respiratory control index (RCI) in mitochondria isolated from fresh quadriceps femoris muscles. (G) Percentage of type I fibers in gastrocnemius muscle shown by the metachromatic staining. Oxidative (Type I) fibers were stained dark blue. Data are means ± S.E.M. n = 3-8. *P < 0.05, **P < 0.01 vs WT. Figure 4: Dietary capsaicin enhances exercise endurance and reduces blood lactic acid and triglycerides through TRPV1 activation. (A, B) Exercise endurance test with treadmill exercise. WT (A) and TRPV1−/− mice (B) on a regular diet (Con) and a capsaicin diet (Cap) for indicated months were tested. Running distance before reaching exhaustion was recorded. Data are presented as the means ± S.E.M. for 6-10 mice. *P < 0.05 vs Con. (C) Oxygen consumption (ml/kg/min) examined when mice ran for 30 min at a speed of 10 m/min. (D) Average daily food intake (g/d) per mouse determined during the last week of each month. (E-H) Body weight and blood levels of lactic acid, triglycerides and glucose. Mice were treated with control or capsaicin diet for 4 months. Data are means ± S.E.M. for 5-9 mice. *P < 0.05 vs Con. Figure 5: Transgenic TRPV1 gene increases PGC-1α expression, oxidative fibers and exercise endurance. (A) Immunoblot of TRPV1 and PGC-1α in skeletal muscle from TRPV1-tg and their wild-type littermates (WT). *P < 0.05, **P < 0.01 vs WT. (B) Metachromatic staining of gastrocnemius muscle. Type I fibers were stained dark blue. (C) Exercise endurance, (D) oxygen consumption, (E) body weight and (F) average daily food intake in TRPV1 transgenic mice and their WT littermates. *P < 0.05, **P < 0.01 vs WT. Mice were fed a regular diet until they reached 6 months of age. Data are means ± S.E.M. for 3 mice. Figure 6: TRPV1 activation restores the HFD-induced PGC-1α downregulation, endurance impairment and metabolic disorders. (A) Immunoblot of TRPV1 and PGC-1α in skeletal muscle from WT mice on normal diet (Con) and HFD without (HF) or with capsaicin supplementation (HFC). (B-E) Running endurance (B), body weight (C) and blood levels of triglycerides (D) and insulin (E) in mice. (F) Lipid contents of quadriceps femoris muscles shown by Oil-red O staining. *P < 0.05, **P < 0.01 vs Con; #P < 0.05, ##P < 0.01 vs HF. (G, H) Intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT). *P < 0.05, **P < 0.01 vs HF; #P < 0.05, ##P < 0.01 vs HFC. Data are means ± S.E.M. for three to six mice.
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