Congenital Myopathies 1 – Nemaline

Abstract

seen does not explain the significant phenotypic heterogeneity observed in NM patients or mouse models, suggesting that additional factors determine disease phenotype. Proteomic assessments of skeletal muscles from the Acta1 H40Y, Acta1 D286G, and Neb cKO mouse models of NM identified cellular pathways affected in all mouse models. Interestingly, mitochondrial dysfunction was present in all models, yet different mitochondria-associated proteins were affected. These results suggested that mitochondrial function was differentially impaired in different NM models. Biochemical assays including respirometry, complex activity function of each element of the electron transport chain, glutathione, and citrate synthase were performed to identify specific dysfunctions. Respirometry revealed mitochondrial impairment relative to wildtype counterparts in the Acta1 H40Y and Neb cKO mouse models but not the Acta1 D286G mouse model. Citrate synthase and glutathione show all normal levels in mutant animals relative to their controls, suggesting that the dysfunction lies in the respiratory chain. Electron transport chain analysis is currently ongoing. These studies form a foundation for future work on the impact of mitochondrial dysfunction in NM and its role in phenotype variability in NM, with the ultimate goal of guiding the development of treatment strategies.