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mTOR Inhibition Prolongs Survival and Has Beneficial Effects on Heart Function After Onset of Lamin A/C Gene Mutation Cardiomyopathy in Mice.

Authors :
Wu W
Jin Q
Östlund C
Tanji K
Shin JY
Han J
Leu CS
Kushner J
Worman HJ
Source :
Circulation. Heart failure [Circ Heart Fail] 2024 Apr; Vol. 17 (4), pp. e011110. Date of Electronic Publication: 2024 Apr 03.
Publication Year :
2024

Abstract

Background: Mutations in LMNA encoding nuclear envelope proteins lamin A/C cause dilated cardiomyopathy. Activation of the AKT/mTOR (RAC-α serine/threonine-protein kinase/mammalian target of rapamycin) pathway is implicated as a potential pathophysiologic mechanism. The aim of this study was to assess whether pharmacological inhibition of mTOR signaling has beneficial effects on heart function and prolongs survival in a mouse model of the disease, after onset of heart failure.<br />Methods: We treated male Lmna <superscript>H222P/H222P</superscript> mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival.<br />Results: Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% ( P =0.018) reduction in left ventricular end-diastolic diameter and a 39% ( P =0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in Lmna <superscript>H222P/H222P</superscript> mice, by 9% ( P =0.0348) and 11% ( P =0.0206), respectively, compared with placebo (n=20).<br />Conclusions: These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by LMNA mutations and that further study is warranted.<br />Competing Interests: Disclosures Drs Wu and Worman received funding from Navitor Pharmaceuticals. Dr Worman has served as a consultant for J&J Consumer for matters unrelated to this publication. The other authors report no conflicts.

Details

Language :
English
ISSN :
1941-3297
Volume :
17
Issue :
4
Database :
MEDLINE
Journal :
Circulation. Heart failure
Publication Type :
Academic Journal
Accession number :
38567527
Full Text :
https://doi.org/10.1161/CIRCHEARTFAILURE.123.011110