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The mechanistic target of rapamycin (mTOR) signaling pathway plays a central role in aging and a number of different disease states. Rapamycin, which suppresses activity of the mTOR complex 1 (mTORC1), shows preclinical (and sometimes clinical) efficacy in a number of disease models. Among these are  Lmna   −/−   mice, which serve as a mouse model for dystrophy-associated laminopathies. To confirm that elevated mTORC1 signaling is responsible for the pathology manifested in  Lmna   −/−   mice and to decipher downstream genetic mechanisms underlying the benefits of rapamycin, we tested in  Lmna   −/−   mice whether survival could be extended and disease pathology suppressed either by reduced levels of S6K1 or enhanced levels of 4E-BP1, two canonical mTORC1 substrates. Global heterozygosity for  S6K1  ubiquitously extended lifespan of  Lmna   −/−   mice ( Lmna   −/−    S6K1   +/−   mice). This life extension is due to improving muscle, but not heart or adipose, function, consistent with the observation that genetic ablation of  S6K1  specifically in muscle tissue also extended survival of  Lmna   −/−   mice. In contrast, whole-body overexpression of 4E-BP1 shortened the survival of  Lmna   −/−   mice, likely by accelerating lipolysis. Thus, rapamycin-mediated lifespan extension in  Lmna   −/−   mice is in part due to the improvement of skeletal muscle function and can be phenocopied by reduced S6K1 activity, but not 4E-BP1 activation.

Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins