Cardiac mTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington’s Disease

Abstract

SUMMARY 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.

Increased oxidative stress and CaMKII activity contribute to electro‐mechanical defects in cardiomyocytes from a murine model of Huntington's disease

“…This suggests that the cardiovascular disturbances might be a consequence of direct cardiomyocyte abnormalities as well as improper autonomous nervous system input . Moreover, it has been described that cardiac mHTT expression inhibited protein complexes such as mechanistic target of rapamycin complex 1 (mTORC1), limiting heart growth and reducing the heart's ability to compensate for chronic stress . BACHD, a new mouse model of HD, showed functional differences between WT and BACHD hearts starting at 3 months of age, and the aged BACHD mice developed cardiac fibrosis and apoptosis .…”

Effects of mutant huntingtin inactivation on Huntington disease‐related behaviours in the BACHD mouse model

“…Furthermore, Nestin is expressed in peripheral tissues with muscle and endothelial origins such as skeletal muscle and kidney [57], and it is therefore possible that prevention of pathology in these peripheral tissues could contribute to the motor phenotype rescue in the BACHD-Nestin mice. It should also be noted that peripheral pathology has been detected in other non-Nestin-expressing tissues such as the heart, liver and white adipose tissue in HD and it remains possible that pathology in these areas contributes to the non-rescued motor dysfunction in BACHD-Nestin mice [22][23][24][25][26].…”

“…We first aimed to remove mutant HTT early during development in a widespread fashion within the CNS by crossing BACHD mice with Nestin-Cre mice, with the hypothesis that these animals would show significant improvements. The aim was to investigate whether their phenotype would completely normalise given that peripheral pathology has also been suggested to play a role in HD [22][23][24][25][26]. We then refined the design and limited the inactivation of mutant HTT selectively to dopamine D2 receptor-expressing projection neurons of the indirect striatal pathway.…”

Mammalian Target of Rapamycin

“…In these patients, the mutant Huntingtin protein is expressed in heart tissue and causes cardiac malfunction, supporting epidemiologic studies, which reported higher rates of heart disease in this population. 91 Two mouse models of Huntington disease have shown that inactivation of the MTORC1-RHEB complex and the resulting loss of MTORC1 function in cardiac tissue can cause cardiac malfunction in this disease. 91 Finally, other studies have shown that cardiac function is tightly regulated by mTOR and requires glycogen synthase kinase 3 alpha (GSK3A)/B signaling.…”

“…91 Two mouse models of Huntington disease have shown that inactivation of the MTORC1-RHEB complex and the resulting loss of MTORC1 function in cardiac tissue can cause cardiac malfunction in this disease. 91 Finally, other studies have shown that cardiac function is tightly regulated by mTOR and requires glycogen synthase kinase 3 alpha (GSK3A)/B signaling. In GKS3A knockout mice, mTOR is activated and mice have age-related cardiac abnormalities.…”