Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy

C Florian Bentzinger; Klaas Romanino; Dimitri Cloëtta; Shuo Lin; Joseph B Mascarenhas; Filippo Oliveri; Jinyu Xia; Emilio Casanova; Céline F Costa; Marijke Brink; Francesco Zorzato; Michael N Hall; Markus A Rüegg

doi:10.1016/j.cmet.2008.10.002

Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy

Cell Metab. 2008 Nov;8(5):411-24. doi: 10.1016/j.cmet.2008.10.002.

Authors

C Florian Bentzinger¹, Klaas Romanino, Dimitri Cloëtta, Shuo Lin, Joseph B Mascarenhas, Filippo Oliveri, Jinyu Xia, Emilio Casanova, Céline F Costa, Marijke Brink, Francesco Zorzato, Michael N Hall, Markus A Rüegg

Affiliation

¹ Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

PMID: 19046572
DOI: 10.1016/j.cmet.2008.10.002

Abstract

Mammalian target of rapamycin (mTOR) is a central controller of cell growth. mTOR assembles into two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. Here we show that the mTORC1 component raptor is critical for muscle function and prolonged survival. In contrast, muscles lacking the mTORC2 component rictor are indistinguishable from wild-type controls. Raptor-deficient muscles become progressively dystrophic, are impaired in their oxidative capacity, and contain increased glycogen stores, but they express structural components indicative of oxidative muscle fibers. Biochemical analysis indicates that these changes are probably due to loss of activation of direct downstream targets of mTORC1, downregulation of genes involved in mitochondrial biogenesis, including PGC1alpha, and hyperactivation of PKB/Akt. Finally, we show that activation of PKB/Akt does not require mTORC2. Together, these results demonstrate that muscle mTORC1 has an unexpected role in the regulation of the metabolic properties and that its function is essential for life.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins / genetics
Carrier Proteins / physiology*
Enzyme Activation
Gene Expression Regulation
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Knockout
Mitochondria / physiology*
Multiprotein Complexes
Muscle, Skeletal / metabolism*
Muscle, Skeletal / pathology
Muscular Dystrophies / metabolism*
Muscular Dystrophies / pathology
Oncogene Protein v-akt / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phosphorylation
Proteins
Proto-Oncogene Proteins c-akt / metabolism
Rapamycin-Insensitive Companion of mTOR Protein
Regulatory-Associated Protein of mTOR
TOR Serine-Threonine Kinases
Trans-Activators / metabolism
Transcription Factors / genetics
Transcription Factors / physiology*

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Multiprotein Complexes
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Proteins
Rapamycin-Insensitive Companion of mTOR Protein
Regulatory-Associated Protein of mTOR
Rptor protein, mouse
Trans-Activators
Transcription Factors
rictor protein, mouse
Mechanistic Target of Rapamycin Complex 1
Oncogene Protein v-akt
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases