Cho Yoshitake, Hazen Bethany C, Gandra Paulo G, Ward Samuel R, Schenk Simon, Russell Aaron P, Kralli Anastasia
*Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA; Department of Orthopedic Surgery, School of Medicine, University of California, San Diego, La Jolla, California, USA; and Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
*Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA; Department of Orthopedic Surgery, School of Medicine, University of California, San Diego, La Jolla, California, USA; and Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia
FASEB J. 2016 Feb;30(2):674-87. doi: 10.1096/fj.15-276360. Epub 2015 Oct 19.
Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole-body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age-related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno-associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4-wk-old mice. Compared to control vector, AAV1-Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40-80%). Moreover, AAV1-Perm1-transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31%, respectively), without prominent changes in fiber-type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.
骨骼肌线粒体含量和氧化能力是肌肉功能和全身健康的重要决定因素。耐力运动可增强线粒体含量和功能，而在肌肉功能受损的状态或疾病中，如肌病、肌肉萎缩症、神经肌肉疾病以及与年龄相关的肌肉萎缩，线粒体含量和功能则会受损。因此，阐明控制肌肉线粒体含量和氧化功能的机制可为影响肌肉健康的状态和疾病提供新的见解。在过去的研究中，我们鉴定出Perm1（PPARGC1和ESRR诱导的调节因子，肌肉1）是骨骼肌中由耐力运动诱导的基因，并在培养的肌管中调节线粒体氧化功能。Perm1在体内调节肌肉线粒体含量和功能的能力尚不清楚。在本研究中，我们使用腺相关病毒（AAV）载体来增加4周龄小鼠骨骼肌中Perm1的表达。与对照载体相比，AAV1-Perm1导致线粒体含量和氧化能力显著增加（增加40-80%）。此外，AAV1-Perm1转导的肌肉显示毛细血管密度增加和抗疲劳能力增强（分别增加33%和31%），而纤维类型组成没有明显变化。这些发现表明Perm1选择性地调节线粒体生物发生和氧化功能，并表明Perm1参与了耐力运动所引起的肌肉适应性变化。
