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

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

  • Circ Heart Fail. 2024 Apr;17(4):e011110. doi: 10.1161/CIRCHEARTFAILURE.123.011110.
Wei Wu 1 2,  Qi Jin 1 2,  Cecilia Östlund 1 2,  Kurenai Tanji 2,  Ji-Yeon Shin 1,  Jiying Han 3,  Cheng-Shiun Leu 3,  Jared Kushner # 1,  Howard J Worman # 1 2
Affiliations

Affiliations

  • 1 Department of Medicine, Vagelos College of Physicians and Surgeons, (W.W., Q.J., C.Ö., J.-Y.S., J.K., H.J.W.), Columbia University, New York, NY.
  • 2 Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons (W.W., Q.J., C.Ö., K.T., H.J.W.), Columbia University, New York, NY.
  • 3 Department of Biostatistics, Mailman School of Public Health (J.H., C.-S.L.), Columbia University, New York, NY.
  • # Contributed equally.
PMID: 38567527 DOI: 10.1161/CIRCHEARTFAILURE.123.011110
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.

Methods: We treated male LmnaH222P/H222P 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.

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 LmnaH222P/H222P mice, by 9% (P=0.0348) and 11% (P=0.0206), respectively, compared with placebo (n=20).

Conclusions: These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by LMNA mutations and that further study is warranted.

Keywords

cardiomyopathies; everolimus; lamins; mice; nuclear envelope.

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