Research ArticleLaminopathies

Temsirolimus Activates Autophagy and Ameliorates Cardiomyopathy Caused by Lamin A/C Gene Mutation

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Science Translational Medicine  25 Jul 2012:
Vol. 4, Issue 144, pp. 144ra102
DOI: 10.1126/scitranslmed.3003875

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Taking a Bite Out of Cardiomyopathy

Mutations that affect nuclear lamins, which form the mesh-like layer inside the nuclear membrane, cause a surprising variety of disorders, together termed laminopathies. Physically stressed tissues such as muscle, where maintenance of nuclear envelope stability is important, are often affected—indeed, lamins are found exclusively in animals, presumably as an adaptation to mobility. Although exactly how altered lamins cause disease is not yet clear, cell signaling pathways seem to be affected. The new work by Choi et al. sheds light on a major signaling pathway affected in one laminopathy and indicates possible therapeutic agents.

The most common laminopathy, dilated cardiomyopathy, is caused by certain mutations in the A-type lamin gene LMNA. Here, the heart is enlarged and weakened, often leading to heart failure and premature death. Because altered signaling by the kinase AKT has been associated with other forms of cardiomyopathy, Choi and colleagues examined such signaling in a mouse model in which cardiomyopathy is caused by an Lmna point mutation. They found abnormally enhanced AKT activation in the hearts of these mice, even before the onset of detectable cardiomyopathy, as well as hyperactivation of an AKT target, the kinase mammalian target of rapamycin (mTOR). Treatment with temsirolimus, a derivative of the mTOR complex 1 (mTORC1) inhibitor rapamycin, reduced mTOR activation and prevented cardiac defects. mTORC1 inhibits autophagy, a highly regulated process in which cellular components are degraded to maintain tissue homeostasis. The authors found that autophagy was deficient in the hearts of the diseased mice and that temsirolimus treatment reactivated autophagy. The enhanced autophagy correlated with improved heart function.

Choi and co-workers also observed enhanced AKT activation in heart tissue from patients with dilated cardiomyopathy caused by mutations in LMNA, supporting the idea that mTORC1 inhibitors might be useful for treating this condition in humans. This concept is reinforced by a related work described by Ramos et al. in this issue.