Cardiac MTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington's Disease

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Apr 26

PMID 29694882

Citations 11

Authors

Daniel D Child

John H Lee

Christine J Pascua

Yong Hong Chen

Alejandro Mas Monteys

Beverly L Davidson

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is a dominantly inherited neurological disorder caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). But in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed, impairs other organ systems. Indeed, epidemiological and animal model studies suggest higher incidence of and mortality from heart disease in HD. Here, we show that the protein complex mTORC1 is dysregulated in two HD mouse models through a mechanism that requires intrinsic mHTT expression. Moreover, restoring cardiac mTORC1 activity with constitutively active Rheb prevents mortality and relieves the mHTT-induced block to hypertrophic adaptation to cardiac stress. Finally, we show that chronic mTORC1 dysregulation is due in part to mislocalization of endogenous Rheb. These data provide insight into the increased cardiac-related mortality of HD patients, with cardiac mHTT expression inhibiting mTORC1 activity, limiting heart growth, and decreasing the heart's ability to compensate to chronic stress.

Citing Articles

Atrial fibrillation risk model based on LASSO and SVM algorithms and immune infiltration of key mitochondrial energy metabolism genes.

Yang X, Lan W, Lin C, Zhu C, Ye Z, Chen Z Sci Rep. 2025; 15(1):6681.

PMID: 39994392 PMC: 11850640. DOI: 10.1038/s41598-025-91047-3.

Santalum album L. alleviates cardiac function injury in heart failure by synergistically inhibiting inflammation, oxidative stress and apoptosis through multiple components.

Ding B, Jiang L, Zhang N, Zhou L, Luo H, Wang H Chin Med. 2024; 19(1):98.

PMID: 39010069 PMC: 11251102. DOI: 10.1186/s13020-024-00968-0.

Huntington's disease phenotypes are improved via mTORC1 modulation by small molecule therapy.

St-Cyr S, Child D, Giaime E, Smith A, Pascua C, Hahm S PLoS One. 2022; 17(8):e0273710.

PMID: 36037192 PMC: 9423655. DOI: 10.1371/journal.pone.0273710.

Metabolism in Huntington's disease: a major contributor to pathology.

Singh A, Agrawal N Metab Brain Dis. 2021; 37(6):1757-1771.

PMID: 34704220 DOI: 10.1007/s11011-021-00844-y.

MicroRNAs Regulating Autophagy in Neurodegeneration.

Lai Q, Kovzel N, Konovalov R, Vinnikov I Adv Exp Med Biol. 2021; 1208:191-264.

PMID: 34260028 DOI: 10.1007/978-981-16-2830-6_11.

References

Li Y, Wang Y, Kim E, Beemiller P, Wang C, Swanson J . Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J Biol Chem. 2007; 282(49):35803-13. DOI: 10.1074/jbc.M705231200. View

She P, Zhang Z, Marchionini D, Diaz W, Jetton T, Kimball S . Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. Am J Physiol Endocrinol Metab. 2011; 301(1):E49-61. PMC: 3129844. DOI: 10.1152/ajpendo.00630.2010. View

McBride J, Pitzer M, Boudreau R, Dufour B, Hobbs T, Ojeda S . Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. Mol Ther. 2011; 19(12):2152-62. PMC: 3242667. DOI: 10.1038/mt.2011.219. View

Boudreau R, McBride J, Martins I, Shen S, Xing Y, Carter B . Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol Ther. 2009; 17(6):1053-63. PMC: 2835182. DOI: 10.1038/mt.2009.17. View

Mihm M, Amann D, Schanbacher B, Altschuld R, Bauer J, Hoyt K . Cardiac dysfunction in the R6/2 mouse model of Huntington's disease. Neurobiol Dis. 2006; 25(2):297-308. PMC: 1850107. DOI: 10.1016/j.nbd.2006.09.016. View

Melkani G, Trujillo A, Ramos R, Bodmer R, Bernstein S, Ocorr K . Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart. PLoS Genet. 2013; 9(12):e1004024. PMC: 3868535. DOI: 10.1371/journal.pgen.1004024. View

Ribchester R, Thomson D, Wood N, Hinks T, Gillingwater T, Wishart T . Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation. Eur J Neurosci. 2004; 20(11):3092-114. DOI: 10.1111/j.1460-9568.2004.03783.x. View

Mielcarek M, Bondulich M, Inuabasi L, Franklin S, Muller T, Bates G . The Huntington's disease-related cardiomyopathy prevents a hypertrophic response in the R6/2 mouse model. PLoS One. 2014; 9(9):e108961. PMC: 4182603. DOI: 10.1371/journal.pone.0108961. View

Boluyt M, Zheng J, Younes A, Long X, ONeill L, Silverman H . Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes. Evidence for involvement of p70 S6 kinase. Circ Res. 1997; 81(2):176-86. DOI: 10.1161/01.res.81.2.176. View

10.

Walker F . Huntington's disease. Lancet. 2007; 369(9557):218-28. DOI: 10.1016/S0140-6736(07)60111-1. View

11.

Basso A, Mirza A, Liu G, Long B, Bishop W, Kirschmeier P . The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem. 2005; 280(35):31101-8. DOI: 10.1074/jbc.M503763200. View

12.

Song X, Kusakari Y, Xiao C, Kinsella S, Rosenberg M, Scherrer-Crosbie M . mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol. 2010; 299(6):C1256-66. PMC: 3006320. DOI: 10.1152/ajpcell.00338.2010. View

13.

Chaturvedi R, Calingasan N, Yang L, Hennessey T, Johri A, Beal M . Impairment of PGC-1alpha expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington's disease following chronic energy deprivation. Hum Mol Genet. 2010; 19(16):3190-205. PMC: 2915615. DOI: 10.1093/hmg/ddq229. View

14.

Schilling G, Becher M, Sharp A, Jinnah H, Duan K, Kotzuk J . Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999; 8(3):397-407. DOI: 10.1093/hmg/8.3.397. View

15.

Lanska D, Lanska M, Lavine L, Schoenberg B . Conditions associated with Huntington's disease at death. A case-control study. Arch Neurol. 1988; 45(8):878-80. DOI: 10.1001/archneur.1988.00520320068017. View

16.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

17.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

18.

Menalled L, Kudwa A, Miller S, Fitzpatrick J, Watson-Johnson J, Keating N . Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175. PLoS One. 2013; 7(12):e49838. PMC: 3527464. DOI: 10.1371/journal.pone.0049838. View

19.

Wilhelm M, Schlegl J, Hahne H, Gholami A, Lieberenz M, Savitski M . Mass-spectrometry-based draft of the human proteome. Nature. 2014; 509(7502):582-7. DOI: 10.1038/nature13319. View

20.

Lin A, Yao J, Zhuang L, Wang D, Han J, Lam E . The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene. 2013; 33(24):3183-94. PMC: 4365448. DOI: 10.1038/onc.2013.273. View