Faculty Collaboration Database

Different Mouse Models of Nemaline Myopathy Harboring Acta1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology. Am J Pathol 2023 Oct;193(10):1548-1567

Date

07/08/2023

Pubmed ID

37419385

Pubmed Central ID

PMC10548277

DOI

10.1016/j.ajpath.2023.06.008

Scopus ID

2-s2.0-85171370030 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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.

Author List

Tinklenberg JA, Slick RA, Sutton J, Zhang L, Meng H, Beatka MJ, Vanden Avond M, Prom MJ, Ott E, Montanaro F, Heisner J, Toro R, Hardeman EC, Geurts AM, Stowe DF, Hill RB, Lawlor MW

Authors

Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
David F. Stowe MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actins
Animals
Disease Models, Animal
Mice
Muscle, Skeletal
Mutation
Myopathies, Nemaline
Proteomics