The Interplay Between PGC-1 and Autophagy During Metabolic Alterations in Skeletal Muscle

PGC-1α is a transcriptional co-activator well established as a potent regulator of oxidative metabolism in skeletal muscle. This co-activator mediates metabolic adaptation to exercise by orchestrating mitochondrial biogenesis. PGC-1α is also integral for the maintenance of muscle mass and function during atrophic conditions. Autophagy is a highly conserved proteolytic pathway responsible for the degradation of dysfunctional organelles and protein aggregates through the lysosomal machinery. Autophagy is upregulated during metabolic distress and is essential for cell survival. While PGC-1α has been extensively studied in the context of skeletal muscle adaptations, its role in autophagy has not been dissected. To this end, the purpose of this dissertation was to examine the interplay between PGC-1α and autophagy in skeletal muscle in the spectrum of muscle contractile states. We first assessed the role of PGC-1α in the regulation of autophagy and mitophagy during chronic muscle disuse in the form of denervation. To do this we denervated wildtype (WT), PGC-1α knockout (KO) as well as PGC-1α overexpressing (Tg) animals. We found that autophagy and mitophagy flux were compromised in KO animals both basally, and in response to denervation, resulting in a myopathic phenotype. In the Tg animals we uncovered enhanced levels of certain autophagy and lysosomal markers, but surprisingly noticed reduced targeting of mitochondria for degradation. Overall we concluded that PGC-1α is important for the fine-tuning of autophagy in skeletal muscle based on cellular metabolic state, but that it is not required for this process. Next we evaluated the role of PGC-1α in mitochondrial turnover following an acute bout of exhaustive exercise. We found that in the absence of PGC-1α, exercise-induced mitochondrial turnover was compromised, as evident by reduced expression of mitochondrial genes and diminished autophagy/mitophagy induction, as well as flux. Collectively, our data demonstrate that PGC-1α is instrumental in maintaining mitochondrial health in skeletal muscle through enhancing organelle turnover. Moreover, PGC-1α can fine-tune autophagy/mitophagy in a manner that is specific to cellular metabolic state.