Abstract
BackgroundAlterations in skeletal muscle contractile activity necessitate an efficient remodeling mechanism. In particular, mitochondrial turnover is essential for tissue homeostasis during muscle adaptations to chronic use and disuse. While mitochondrial biogenesis appears to be largely governed by the transcriptional co-activator peroxisome proliferator co-activator 1 alpha (PGC-1α), selective mitochondrial autophagy (mitophagy) is thought to mediate organelle degradation. However, whether PGC-1α plays a direct role in autophagy is currently unclear.MethodsTo investigate the role of the co-activator in autophagy and mitophagy during skeletal muscle remodeling, PGC-1α knockout (KO) and overexpressing (Tg) animals were unilaterally denervated, a common model of chronic muscle disuse.ResultsAnimals lacking PGC-1α exhibited diminished mitochondrial density alongside myopathic characteristics reminiscent of autophagy-deficient muscle. Denervation promoted an induction in autophagy and lysosomal protein expression in wild-type (WT) animals, which was partially attenuated in KO animals, resulting in reduced autophagy and mitophagy flux. PGC-1α overexpression led to an increase in lysosomal capacity as well as indicators of autophagy flux but exhibited reduced localization of LC3II and p62 to mitochondria, compared to WT animals. A correlation was observed between the levels of the autophagy-lysosome master regulator transcription factor EB (TFEB) and PGC-1α in muscle, supporting their coordinated regulation.ConclusionsOur investigation has uncovered a regulatory role for PGC-1α in mitochondrial turnover, not only through biogenesis but also via degradation using the autophagy-lysosome machinery. This implies a PGC-1α-mediated cross-talk between these two opposing processes, working to ensure mitochondrial homeostasis during muscle adaptation to chronic disuse.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-015-0033-y) contains supplementary material, which is available to authorized users.
Highlights
Alterations in skeletal muscle contractile activity necessitate an efficient remodeling mechanism
Lack of proliferator gamma coactivator-1α (PGC-1α) results in diminished mitochondrial content, reduced muscle mass, and a myopathic phenotype In order to ascertain the role of PGC-1α in skeletal muscle autophagy, 8-month-old whole-body PGC-1α KO and WT animals were unilaterally denervated for 7 days by severing the sciatic nerve of one hindlimb, with the contralateral limb serving as an internal Con
When corrected for body weight, the muscle mass of KO animals was greater than that of the WT littermates; this was a result of their reduced body weight and not due to muscle hypertrophy, as fiber cross-sectional areas were smaller in mice lacking PGC-1α (Additional file 1: Figure S1A-C)
Summary
Alterations in skeletal muscle contractile activity necessitate an efficient remodeling mechanism. Mitochondrial turnover is essential for tissue homeostasis during muscle adaptations to chronic use and disuse. Muscle is an indispensable metabolic center that possesses a remarkable capacity to adapt to alterations in its milieu, a property known as muscle plasticity. This type of malleability to cues such as contraction, nutrient availability, or hormonal stimuli requires efficient cellular remodeling and a rapid shift in metabolic profile. While mitophagy is important for proper tissue remodeling and organelle turnover, the regulation of this process in the skeletal muscle remains largely elusive
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