Fiber Type Conversion by PGC-1α Activates Lysosomal and Autophagosomal Biogenesis in Both Unaffected and Pompe Skeletal Muscle

Fundação Oswaldo Cruz, Brazil
PLoS ONE (Impact Factor: 3.23). 12/2010; 5(12):e15239. DOI: 10.1371/journal.pone.0015239
Source: PubMed


PGC-1α is a transcriptional co-activator that plays a central role in the regulation of energy metabolism. Our interest in this protein was driven by its ability to promote muscle remodeling. Conversion from fast glycolytic to slow oxidative fibers seemed a promising therapeutic approach in Pompe disease, a severe myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) which is responsible for the degradation of glycogen. The recently approved enzyme replacement therapy (ERT) has only a partial effect in skeletal muscle. In our Pompe mouse model (KO), the poor muscle response is seen in fast but not in slow muscle and is associated with massive accumulation of autophagic debris and ineffective autophagy. In an attempt to turn the therapy-resistant fibers into fibers amenable to therapy, we made transgenic KO mice expressing PGC-1α in muscle (tgKO). The successful switch from fast to slow fibers prevented the formation of autophagic buildup in the converted fibers, but PGC-1α failed to improve the clearance of glycogen by ERT. This outcome is likely explained by an unexpected dramatic increase in muscle glycogen load to levels much closer to those observed in patients, in particular infants, with the disease. We have also found a remarkable rise in the number of lysosomes and autophagosomes in the tgKO compared to the KO. These data point to the role of PGC-1α in muscle glucose metabolism and its possible role as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. These findings may have implications for therapy of lysosomal diseases and other disorders with altered autophagy.

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    • "A concomitant dramatic increase in the number of lysosomes in the PGC-1α- overexpressing muscle accounts for this apparent paradox. However, overexpression of PGC-1α in the diseased muscle failed to improve the ERT, mainly because of the considerable increase in the lysosomal glycogen load (Takikita et al., 2010). Although disappointing , these results are interesting in two respects: (1) a slight PGC-1α-induced increase in the levels of cytoplasmic glycogen (seen in wild type muscle) leads to a massive accumulation of lysosomal glycogen in GAA-deficient muscle, suggesting a high rate of lysosomal glycogen disposal in skeletal muscle. "
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    ABSTRACT: Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage - impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits - a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy.
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    • "The best explored signaling networks involved in the process are related to the Forkhead box O family, the transforming growth factor beta family, and nuclear factor-kappaB [29] [30] [31] [32] [33]. Type II myofibers are more sensitive to these mechanisms and a significant factor contributing the resistance of Type I fibers is the activity of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a well described transcriptional coactivator required for mitochondrial biogenesis, protection from proteolysis and maintenance of the slow twitch, oxidative fiber phenotype of Type I myofibers [34] [35] [36] [37]. This is a descriptive study and therefore its principal limitation is that it cannot establish cause and effect linkages between arterial blockages, oxidative damage, myofiber type degeneration and PAD clinical manifestations. "
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    ABSTRACT: Peripheral artery disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in the arteries supplying the legs, affects approximately 5% of Americans. We have previously, demonstrated that a myopathy characterized by myofiber oxidative damage and degeneration is central to PAD pathophysiology.
    Full-text · Article · Jul 2014
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    • "So does PGC-1α. Expressing PGC-1α in muscle increased the number of lysosomes and autophagosomes (Takikita et al., 2010). These data point to the role of PGC-1α as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. "
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    ABSTRACT: During endurance and resistance exercise training, AMPK and mTOR signaling were known as selective pathways implicating the differentiation of exercise-induced phenotype in skeletal muscle. Among the previous studies, however, the differences in exercise protocol, the individuality and the genetic heterogeneity within species make it difficult to reach a consistent conclusion in the roles of AMPK and mTOR signaling. In this review, we aim not to reanalyze the previous articles and present the research progress of AMPK and mTOR signaling in exercise, but to propose an abstract general hypothesis for exercise-induced phenotype. Generally, exercise- induced skeletal muscle phenotype is independent of one and a few genes, proteins and signaling pathways. Convergent adaptation will better summarize the specificity of skeletal muscle phenotype in response to a single mode of exercise. Backward adaptation will open a new concept to illustrate the process of exercise-induced adaptation, such as mitochondrial quality control and muscle mass homeostasis.
    Full-text · Article · Dec 2013 · SpringerPlus
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