Pharmacological activation of pyruvate dehydrogenase by dichloroacetate protects against obesity-induced muscle atrophy in vitro and in vivo

• Published in: European journal of pharmacology Vol. 979; p. 176854
• Main Authors: Yang, Jung-Mou, Han, I-Shan, Chen, Tsung-Hua, Hsieh, Po-Shiuan, Tsai, Min-Chien, Chien, Hung-Che
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2024
• Subjects: Animals; Autophagy - drug effects; Cell Line; Dichloroacetate; Dichloroacetic Acid - pharmacology; Dichloroacetic Acid - therapeutic use; Diet, High-Fat - adverse effects; Enzyme Activation - drug effects; Male; Mice; Mice, Inbred C57BL; Muscle atrophy; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - drug therapy; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular Atrophy - prevention & control; Obesity; Obesity - complications; Obesity - drug therapy; Pyruvate dehydrogenase; Pyruvate Dehydrogenase Complex - metabolism; Dichloroacetate; Obesity; Pyruvate dehydrogenase; Muscle atrophy
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.176854

Obesity-induced muscle atrophy leads to physical impairment and metabolic dysfunction, which are risky for older adults. The activity of pyruvate dehydrogenase (PDH), a critical regulator of glucose metabolism, is reduced in obesity. Additionally, PDH activator dichloroacetate (DCA) improves metabolic dysfunction. However, the effects of PDH activation on skeletal muscles in obesity remain unclear. Thus, this study aimed to evaluate the effects of PDH activation by DCA treatment on obesity-induced muscle atrophy in vitro and in vivo and elucidate the possible underlying mechanisms. Results showed that PDH activation by DCA treatment ameliorated muscle loss, decreased the cross-sectional area, and reduced grip strength in C57BL/6 mice fed a high-fat diet (HFD). Elevation of muscle atrophic factors atrogin-1 and muscle RING-finger protein-1 (MuRF-1) and autophagy factors LC3BII and p62 were abrogated by DCA treatment in palmitate-treated C2C12 myotubes and in the skeletal muscles of HFD-fed mice. Moreover, p-Akt, p-FoxO1, and p-FoxO3 protein levels were reduced and p-NF-κB p65 and p-p38 MAPK protein levels were elevated in palmitate-treated C2C12 myotubes, which were restored by DCA treatment. However, the protective effects of DCA treatment against myotube atrophy were reversed by treatment with Akt inhibitor MK2206. Taken together, our study demonstrated that PDH activation by DCA treatment can alleviate obesity-induced muscle atrophy. It may serve as a basis for developing novel strategies to prevent obesity-associated muscle loss.