Mitochondrial glycerol 3-phosphate dehydrogenase promotes skeletal muscle regeneration

While adult mammalian skeletal muscle is stable due to its post-mitotic nature, muscle regeneration is still essential throughout life for maintaining functional fitness. During certain diseases, such as the modern pandemics of obesity and diabetes, the regeneration process becomes impaired, leading to the loss of muscle function and contributes to the global burden of these diseases. However, the underlying mechanisms of the impairment are not well defined. Here we identify mGPDH as a critical regulator of skeletal muscle regeneration. Specifically, it regulates myogenic markers and myoblast differentiation by controlling mitochondrial biogenesis via CaMKKβ/AMPK. mGPDH-/- attenuated skeletal muscle regeneration in vitro and in vivo while mGPDH overexpression ameliorated dystrophic pathology in mdx mice. Moreover, in patients and animal models of obesity and diabetes, mGPDH expression in skeletal muscle was reduced, further suggesting a direct correlation between its abundance and muscular regeneration capability. Rescuing mGPDH expression in obese and diabetic mice led to a significant improvement in their muscle regeneration. Our study provides a potential therapeutic target for skeletal muscle regeneration impairment during obesity and diabetes.

尽管成年哺乳动物骨骼肌因具备有丝分裂后特性而保持稳态，但肌肉再生对于终生维持机体生理机能仍至关重要。在肥胖与糖尿病等当前全球性流行疾病中，肌肉再生过程会出现受损，进而导致肌肉功能丧失，并加剧这类疾病的全球疾病负担。然而，此类再生损伤的潜在分子机制尚未被充分阐明。本研究鉴定出线粒体甘油-3-磷酸脱氢酶（mGPDH）为骨骼肌再生的关键调控因子。具体而言，其可通过CaMKKβ/AMPK通路调控线粒体生物发生，进而影响肌源性标志物表达与成肌细胞分化。体外与体内实验均证实，mGPDH敲除（mGPDH-/-）可削弱骨骼肌再生能力，而过表达mGPDH则可改善mdx小鼠的肌营养不良病理表型。此外，在肥胖与糖尿病患者及相关动物模型的骨骼肌组织中，mGPDH的表达水平显著降低，进一步提示其表达丰度与肌肉再生能力存在直接相关性。在肥胖与糖尿病小鼠中恢复mGPDH的表达，可显著改善其肌肉再生功能。本研究为肥胖与糖尿病相关的骨骼肌再生损伤提供了潜在治疗靶点。