Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

Abstract

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.—Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. FASEB J. 30, 674‐687 (2016). http://www.fasebj.org

A mini review: Proteomics approaches to understand disused vs. exercised human skeletal muscle

“…By using adeno-associated virus-mediated gene delivery, we found that overexpression of Perm1 enhances mitochondrial biogenesis and increases oxphos protein in skeletal muscle, mimicking endurance exercise training (Fig. 2) (17). That being the case, it will be interesting to study the role of differentially expressed proteins that are identified by proteomics approaches in exercise adaptation and skeletal muscle disuse, by using overexpression and knock-down or knockout methods.…”

“…In a previous study performed by our group, we identified a novel skeletal muscle enriched protein, Perm1 (PGC1 and ERR induced regulator, muscle 1), which is induced by long-term endurance exercise training in mouse skeletal muscle (Fig. 2) (17). Interestingly, Schild et al (57) and Brinkmann et al (8) also showed that human PERM1 (c1orf170) was upregulated by exercise training in human skeletal muscle, confirming Perm1 is regulated by exercise training in humans and mice.…”

“…Perm1 (B) and oxphos (C) protein levels were determined in muscle lysates by Western blotting, using antibodies indicated. Figure adapted from (17). Data are the means Ϯ SE (n ϭ 4; *P Ͻ 0.05).…”

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“…PERM1 regulates the expression of selective PPARGC1A/B and ESRRA/B/G target genes with roles in glucose and lipid metabolism, energy transfer, contractile function, muscle mitochondrial biogenesis and oxidative capacity 31 . PERM1 also enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance when over-expressed in mice 32 . Finally, we also identified MDH1 , encoding malate dehydrogenase, which together with the mitochondrial MDH2 , regulates the supply of NADPH and acetyl-CoA to the cytoplasm, thus modulating fatty acid synthesis 33 .…”

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