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Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function

Romanino, Klaas and Mazelin, Laetitia and Albert, Verena and Conjard-Duplany, Agnès and Lin, Shuo and Bentzinger, C. Florian and Handschin, Christoph and Puigserver, Pere and Zorzato, Francesco and Schaeffer, Laurent and Gangloff, Yann-Gaël and Rüegg, Markus A.. (2011) Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function. Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, H. 51. pp. 20808-20813.

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Official URL: http://edoc.unibas.ch/dok/A5848991

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Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is central to the control of cell, organ, and body size. Skeletal muscle-specific inactivation of mTORC1 in mice results in smaller muscle fibers, fewer mitochondria, increased glycogen stores, and a progressive myopathy that causes premature death. In mTORC1-deficient muscles, peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC-1?), which regulates mitochondrial biogenesis and glucose homeostasis, is strongly down-regulated. Here we tested whether induction of mitochondrial biogenesis pharmacologically or by the overexpression of PGC-1? is sufficient to reverse the phenotype of mice deficient for mTORC1. We show that both approaches normalize mitochondrial function, such as oxidative capacity and expression of mitochondrial genes. However, they do not prevent or delay the progressive myopathy. In addition, we find that mTORC1 has a much stronger effect than PGC-1? on the glycogen content in muscle. This effect is based on the strong activation of PKB/Akt in mTORC1-deficient mice. We also show that activation of PKB/Akt not only affects glycogen synthesis but also diminishes glycogen degradation. Thus, our work provides strong functional evidence that mitochondrial dysfunction in mice with inactivated mTORC1 signaling is caused by the down-regulation of PGC-1?. However, our data also show that the impairment of mitochondria does not lead directly to the lethal myopathy.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Growth & Development (Handschin)
05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
03 Faculty of Medicine > Departement Biomedizin > Associated Research Groups > Pharmakologie (Handschin)
UniBasel Contributors:Handschin, Christoph and Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:National Academy of Sciences
ISSN:0027-8424
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:31 Dec 2015 10:50
Deposited On:14 Sep 2012 07:15

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