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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: 3.53). 12/2010; 5(12):e15239. DOI: 10.1371/journal.pone.0015239
Source: PubMed

ABSTRACT 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 (GAA) 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 (ERT) 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.
    Frontiers in Aging Neuroscience 07/2014; 6:177. DOI:10.3389/fnagi.2014.00177 · 2.84 Impact Factor
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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.
    07/2014; 2(1). DOI:10.1016/j.redox.2014.07.002
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    • "In skeletal muscles, PGC1a converts fast glycolic fibers to slow oxidative fibers and, in addition, is able to slow protein degradation and protect from atrophy-induced ageing (Takikita et al., 2010). PGC1a overexpression in Gaa-deficient muscles prevents the formation of autophagic buildup through an upregulation of the autophagy flux, but fails to improve the clearance of glycogen; instead, it increases the lysosomal glycogen load (Takikita et al., 2010). Recently, it has been proposed that transcription factor EB (TFEB) could be an effective therapeutic target for Pompe disease (Spampanato et al., 2013). "
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    ABSTRACT: A number of recent studies have highlighted the importance of autophagy and the ubiquitin-proteasome in the pathogenesis of muscle wasting in different types of inherited muscle disorders. Autophagy is crucial for the removal of dysfunctional organelles and protein aggregates, whereas the ubiquitin-proteasome is important for the quality control of proteins. Post-mitotic tissues, such as skeletal muscle, are particularly susceptible to aged or dysfunctional organelles and aggregation-prone proteins. Therefore, these degradation systems need to be carefully regulated in muscles. Indeed, excessive or defective activity of the autophagy lysosome or ubiquitin-proteasome leads to detrimental effects on muscle homeostasis. A growing number of studies link abnormalities in the regulation of these two pathways to myofiber degeneration and muscle weakness. Understanding the pathogenic role of these degradative systems in each inherited muscle disorder might provide novel therapeutic targets to counteract muscle wasting. In this Commentary, we will discuss the current view on the role of autophagy lysosome and ubiquitin-proteasome in the pathogenesis of myopathies and muscular dystrophies, and how alteration of these degradative systems contribute to muscle wasting in inherited muscle disorders. We will also discuss how modulating autophagy and proteasome might represent a promising strategy for counteracting muscle loss in different diseases.
    Journal of Cell Science 12/2013; 126(Pt 23):5325-33. DOI:10.1242/jcs.114041 · 5.33 Impact Factor
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