Back to Search
Start Over
mTOR Inhibition Prolongs Survival and Has Beneficial Effects on Heart Function After Onset of Lamin A/C Gene Mutation Cardiomyopathy in Mice.
- 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.
- Subjects :
- Mice
Humans
Male
Animals
Everolimus pharmacology
Everolimus therapeutic use
Lamin Type A genetics
Lamin Type A metabolism
MTOR Inhibitors
Mutation
TOR Serine-Threonine Kinases
Mechanistic Target of Rapamycin Complex 1 genetics
Mammals metabolism
Heart Failure
Cardiomyopathies drug therapy
Cardiomyopathies genetics
Cardiomyopathies pathology
Drug-Related Side Effects and Adverse Reactions
Subjects
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