Different Mouse Models of Nemaline Myopathy Harboring Acta1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology.

Autor:	Tinklenberg JA; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Clinical and Translational Science Institute, Medical College of Wisconsin, Milwaukee, Wisconsin., Slick RA; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Clinical and Translational Science Institute, Medical College of Wisconsin, Milwaukee, Wisconsin., Sutton J; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin., Zhang L; Mass Spectrometry and Proteomics Facility, Campus Chemical Instrument Center, The Ohio State University, Columbus, Ohio., Meng H; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin., Beatka MJ; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin., Vanden Avond M; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin., Prom MJ; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin., Ott E; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin., Montanaro F; Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neuroscience Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom., Heisner J; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin., Toro R; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin., Hardeman EC; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia., Geurts AM; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin., Stowe DF; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin., Hill RB; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin., Lawlor MW; Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: mlawlor@mcw.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2023 Oct; Vol. 193 (10), pp. 1548-1567. Date of Electronic Publication: 2023 Jul 05.
DOI:	10.1016/j.ajpath.2023.06.008
Abstrakt:	ACTA1 encodes skeletal muscle-specific α-actin, which polymerizes to form the thin filament of the sarcomere. Mutations in ACTA1 are responsible for approximately 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 patients with NM or NM mouse models. To identify additional biological processes related to NM phenotypic severity, proteomic analysis was performed using muscle protein isolates from wild-type mice in comparison to moderately affected knock-in (KI) Acta1 H40Y and the minimally affected transgenic (Tg) ACTA1 D286G NM mice. 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 wild-type 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 transmembrane potential were all normal or minimally affected in the TgACTA1 D286G mouse model. In contrast, the more severely affected KI.Acta1 H40Y mice displayed significant abnormalities in relation to muscle histology, mitochondrial respirometry, ATP, ADP, and phosphate content, and mitochondrial transmembrane potential. These findings suggest that abnormal energy metabolism is related to symptomatic severity in NM and may constitute a contributor to phenotypic variability and a novel treatment target. (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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