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β-hydroxy-β-methylbutyrate (HMB) improves mitochondrial function in myocytes through pathways involving PPARβ/δ and CDK4

Zhong, Yinzhao, Zeng, Liming, Deng, Jinping, Duan, Yehui, Li, Fengna
Nutrition 2019 v.60 pp. 217-226
antagonists, biogenesis, butyrates, essential amino acids, gene expression, leucine, messenger RNA, metabolic diseases, metabolites, mitochondria, myotubes, obesity, skeletal muscle
Mitochondrial dysfunction in skeletal muscle has emerged as key to the development of obesity and its related metabolic disorders. Leucine (Leu) is an essential amino acid that has been reported to increase mitochondrial biogenesis in muscle cells, as has its metabolite β-hydroxy-β-methylbutyrate (HMB). However, two questions—which one is more potent and what is the cellular mechanisms of the action of Leu and HMB—remain to be answered. Therefore we aimed to investigate the effects of Leu and HMB on mitochondrial function in C2 C12 myotubes and analyze the underlying molecular mechanism.The effects of Leu and HMB on mitochondrial mass, mitochondrial respiration capacity, and the expression of genes related to mitochondrial biogenesis were evaluated in C2 C12 myotubes. Differentiated myotubes were treated with Leu (0.5 mM) or HMB (50 μM) with or without PPARβ/δ antagonist (GSK3787, 1 μM) and CDK4 antagonist (LY2835219, 1.5 μM), respectively, for 24 h. The results indicated that treatment with Leu or HMB significantly increased mitochondrial mass, mitochondrial respiration capacity, and the messenger RNA expression of genes associated with mitochondrial biogenesis (P < 0.05). In addition, these positive effects of Leu or HMB on these parameters were attenuated by GSK3787 and LY2835219 treatments (P < 0.05).Our results provide evidence indicating that as with Leu, HMB alone could increase mitochondrial biogenesis and function via regulation of PPARβ/δ and CDK4 pathways. Moreover, HMB seems to be more potent than Leu in the positive regulation of mitochondrial biogenesis and function in C2 C12 myotubes because the dosage used for HMB was much lower than that for Leu.