Different mouse models of nemaline myopathy harboring Acta1 mutations display differing abnormalities related to mitochondrial biology

Am J Pathol. 2023 Jul 5:S0002-9440(23)00239-0. doi: 10.1016/j.ajpath.2023.06.008. Online ahead of print.ABSTRACTACTA1 encodes skeletal muscle-specific α-actin, which polymerizes to form the thin filament of the sarcomere. Mutations in ACTA1 are responsible for roughly 30% of nemaline myopathy (NM) cases. Previous studies of weakness in NM have focused on muscle structure and contractility, but genetic issues alone do not explain the phenotypic heterogeneity observed in NM patients or mouse models. To identify additional biological processes related to NM phenotypic severity, proteomic analysis was performed using muscle protein isolates from wild type (WT) mice in comparison to moderately affected KI.Acta1H40Y and the minimally affected TgACTA1D286G NM mouse models. This analysis revealed abnormalities in mitochondrial function and stress-related pathways in both mouse models, supporting an in-depth assessment of mitochondrial biology. Interestingly, evaluating each model in comparison to its WT counterpart identified different degrees of mitochondrial abnormality that correlated well with the phenotypic severity of the mouse model. Muscle histology, mitochondrial respiration, electron transport chain function, and mitochondrial membrane potential (ΔΨm) were all normal or minimally affected in the TgACTA1D286G mouse model. In contrast, the more severely affected KI.Acta1H40Y mice displayed significant abnormalities in relation to muscle histology, mitochondrial respirometr...
Source: Am J Pathol - Category: Pathology Authors: Source Type: research