Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Shemesh, Adi; Wang, Yichen; Yang, Yingjuan; Yang, Gong She; Johnson, Danielle; Backer, Jonathan M.; Pessin, Jeffrey E.; Zong, Haihong

doi:10.1152/ajpregu.00212.2014

Cited by 20 publications

(20 citation statements)

References 34 publications

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“…We here analyzed phosphorylation of 2 targets of mTORC1, S6K and 4E-BP1, by exposure to amino acids and insulin, and demonstrated that mTORC1 activation was significantly reduced in myocytes derived from Pom iPSC MyoD . This is consistent with recent reports of suppressed mTORC1 activation in fibroblasts from patients with IOPD 47 , GAA-knockdown C2C12 myoblasts, or GAA-KO mice 48 , 49 . In our study, responses to rhGAA treatment were different between S6K and 4E-BP1, which may be attributed to the more complicated regulation of phosphorylation of 4E-BP1 than that of S6K 50 .…”

Section: Discussionsupporting

confidence: 93%

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells

Yoshida

Awaya

Jonouchi

et al. 2017

Sci Rep

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Pompe disease is caused by an inborn defect of lysosomal acid α-glucosidase (GAA) and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD is still unclear. Here we generated induced pluripotent stem cells (iPSCs) from patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, which was dose-dependently rescued by rhGAA. We further demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in IOPD iPSC-derived myocytes. Comprehensive metabolomic and transcriptomic analyses suggested the disturbance of mTORC1-related signaling, including deteriorated energy status and suppressed mitochondrial oxidative function. In summary, we successfully established an in vitro skeletal muscle model of IOPD using patient-specific iPSCs. Disturbed mTORC1 signaling may contribute to the pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for Pompe disease.

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Section: Discussionsupporting

confidence: 93%

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells

Yoshida

Awaya

Jonouchi

et al. 2017

Sci Rep

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“…Reduced mTORC1 activity has been documented in fibroblasts from Pompe patients and in GAA KO muscle. 48 We, too, observe inhibition of mTORC1 activity in cultured murine KO myotubes and whole muscle from Pompe mice (unpublished data). The link between lysosomal glycogen over-accumulation and reduced mTORC1 activity is supported by the data showing that the deficiency of the putative lysosomal sugar transporter Spinster (Spin) leads to lysosomal accumulation of carbohydrates in the enlarged lysosomes and an mTORC1 dysfunction (lack of its reactivation after prolonged starvation).…”

Section: Calcium Homeostasismentioning

confidence: 84%

Pompe disease: Shared and unshared features of lysosomal storage disorders

Lim

Kakhlon

et al. 2015

Rare Diseases

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Pompe disease, an inherited deficiency of lysosomal acid α-glucosidase (GAA), is a severe metabolic myopathy with a wide range of clinical manifestations. It is the first recognized lysosomal storage disorder and the first neuromuscular disorder for which a therapy (enzyme replacement) has been approved. As GAA is the only enzyme that hydrolyses glycogen to glucose in the acidic environment of the lysosome, its deficiency leads to glycogen accumulation within and concomitant enlargement of this organelle. Since the introduction of the therapy, the overall understanding of the disease has progressed significantly, but the pathophysiology of muscle damage is still not fully understood. The emerging complex picture of the pathological cascade involves disturbance of calcium homeostasis, mitochondrial abnormalities, dysfunctional autophagy, accumulation of toxic undegradable materials, and accelerated production of lipofuscin deposits that are unrelated to aging. The relationship of Pompe disease to other lysosomal storage disorders and potential therapeutic interventions for Pompe disease are discussed.

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“…The information regarding mTOR signaling in Pompe muscle cells is limited to a recent finding of reduced insulin‐stimulated mTORC1 activation in two cellular models of Pompe disease—GAA‐knockdown C2C12 myoblasts and GAA‐deficient human fibroblasts from infantile Pompe patients (Shemesh et al , ). However, neither basal levels of mTOR activity nor the mechanism of mTOR dysregulation was evaluated in these models, which are quite different from the one used in this study—multinucleated KO myotubes displaying enlarged glycogen‐filled lysosomes and defective autophagy—the two major pathologies in the diseased muscle.…”

Section: Discussionmentioning

confidence: 99%

“…Recent data demonstrate that leucine enters the lysosome through the leucine transporter, which is recruited to the lysosomal membrane by the lysosomal protein LAPTM4b (Milkereit et al , ). Leucine supplementation has been recently proposed as a therapeutic approach for Pompe disease (Shemesh et al , ). Our data demonstrate the leucine‐mediated process of mTOR recruitment to the lysosome is already activated in the diseased Pompe muscle cells; therefore, pushing it further does not seem to make much sense, and may even be harmful in the long run.…”

Section: Discussionmentioning

confidence: 99%

Modulation of mTOR signaling as a strategy for the treatment of Pompe disease

Lim

Shirihai

et al. 2017

EMBO Mol Med

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Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases. In this study, we have examined the involvement of the mTOR pathway in the pathophysiology of a severe muscle wasting condition, Pompe disease, caused by excessive accumulation of lysosomal glycogen. Here, we report the dysregulation of mTOR signaling in the diseased muscle cells, and we focus on potential sites for therapeutic intervention. Reactivation of mTOR in the whole muscle of Pompe mice by TSC knockdown resulted in the reversal of atrophy and a striking removal of autophagic buildup. Of particular interest, we found that the aberrant mTOR signaling can be reversed by arginine. This finding can be translated into the clinic and may become a paradigm for targeted therapy in lysosomal, metabolic, and neuromuscular diseases.

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Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Cited by 20 publications

References 34 publications

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells

Pompe disease: Shared and unshared features of lysosomal storage disorders

Modulation of mTOR signaling as a strategy for the treatment of Pompe disease

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