Research ArticleLaminopathies

Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

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Science Translational Medicine  25 Jul 2012:
Vol. 4, Issue 144, pp. 144ra103
DOI: 10.1126/scitranslmed.3003802

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Rapping Down mTORC1 Aids Ailing Muscles

Rapamycin—a bacterial product discovered in soil samples from the eponymous Rapa Nui, or Easter Island—is a markedly versatile drug. Clinically, it is used to prevent organ transplant rejection, treat cancer, and improve angioplasty outcomes; it also increases life span in organisms ranging from yeast to mice. Now, Ramos and colleagues show its potential for treating muscle disease caused by mutations in LMNA.

LMNA encodes A-type lamins, intermediate filament proteins that form the nuclear lamina, a layer just under the nuclear membrane. Different LMNA mutations cause distinct diseases, but reduced A-type lamin function is generally linked to skeletal muscle dystrophy and dilated cardiomyopathy, in which the heart is enlarged and weakened. Mice that lack Lmna likewise develop these conditions, dying young of heart problems. Ramos et al. speculated that signaling pathways involved in muscle remodeling, such as that for the kinase mTOR—the mammalian target of rapamycin—might be dysregulated in Lmna−/− mice, contributing to their problems. mTOR complex 1 (mTORC1) senses information about energy, nutrients, and stress; in response, it regulates cellular processes such as protein synthesis and autophagy (in which cellular components are degraded to reallocate nutrients). The authors found that mTORC1 signaling was hyperactivated in skeletal and heart muscle in Lmna−/− mice. Furthermore, the mTORC1 inhibitor rapamycin decreased mTORC1 signaling, improved skeletal and cardiac muscle function, and increased the life span of these mice. Lmna−/− mice also exhibited defective autophagy, which could be improved by rapamycin. In addition, previous work showed abnormal aggregation of desmin, which normally forms filaments that are important for muscle structure, in these mice. Rapamycin decreased these aggregates.

This study indicates that hyperactive mTORC1 signaling helps to create the phenotypes of Lmna−/− mice. There are no effective treatments for the related conditions in humans; this work—and related findings reported by Choi et al. in this issue—indicate that rapamycin-related compounds might serve such a role.

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