Abstract Body: BACKGROUND: Disruption of cardiac protein homeostasis (proteostasis) contributes to the development of proteotoxic cardiomyopathies. Mutations in molecular chaperones, such as αB-crystallin (Arg120Gly; CryAB^R120G), disrupt proteostatic balance in the heart, leading to cellular disorganization, misfolded protein aggregation, and impaired autophagic clearance. Sigmar1 is a multifunctional chaperone protein implicated in cellular stress responses, mitochondrial homeostasis, and regulation of autophagy. However, the role of Sigmar1 in regulating proteotoxic stress in CryAB^R120G hearts remains poorly understood.
HYPOTHESIS: We hypothesize that Sigmar1 regulates cardiac proteostasis by activating autophagy pathways and thereby protects against CryAB^R120G-induced proteotoxic cardiomyopathy.
METHODS: We generated cardiac-specific inducible Sigmar1 transgenic (Sigmar1^TG) mice and global Sigmar1 knockout (Sigmar1^-/-) mice to investigate the role of Sigmar1 in cardiac proteostasis. In vivo autophagy flux was assessed using GFP-LC3 and mRFP-GFP-LC3 (tf-LC3) reporter mice. Sigmar1^TG and Sigmar1^-/- mice were crossed with CryAB^R120G mice to determine the impact of Sigmar1 modulation in the proteotoxic cardiomyopathy by assessing cardiac functional, histopathological, and ultrastructural analyses.
RESULTS: Sigmar1^TG hearts showed enhanced basal autophagy flux without alterations in cardiac morphology or contractile function, whereas Sigmar1^-/- hearts exhibited impaired autophagy. Sigmar1 activation was associated with upregulation of autophagy-related genes and Sigmar1-LC3B interaction. Sigmar1 expression was significantly reduced in CryAB^R120G hearts. In CryAB^R120G hearts, Sigmar1 overexpression attenuated hypertrophy, fibrosis, aggregate accumulation and contractile dysfunction accompanied by increased autophagy. In contrast, Sigmar1 ablation exacerbated pathological remodeling, aggregate burden, and functional decline, with reduced autophagy flux in CryAB^R120G hearts.
CONCLUSIONS: Sigmar1 plays a key role in regulating cardiac proteostasis and remodeling in proteotoxic cardiomyopathy. Sigmar1 overexpression confers cardioprotection, whereas its ablation aggravates cardiac pathologies. These findings suggest Sigmar1 activation as a potential therapeutic strategy to preserve cardiac function under proteotoxic stress.