Cho Y, Hazen BC, Gandra PG, Ward SR, Schenk S, Russell AP, Kralli A.
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.
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