Proteomic Profiling Uncovers Sexual Dimorphism in the Muscle Response to Wheel Running Exercise in the FLExDUX4 Murine Model of Facioscapulohumeral Muscular Dystrophy

Nishimura, Y ORCID: 0000-0001-8225-7675, Bittel, A, Jagan, A, Chen, YW and Burniston, J ORCID: 0000-0001-7303-9318 (2025) Proteomic Profiling Uncovers Sexual Dimorphism in the Muscle Response to Wheel Running Exercise in the FLExDUX4 Murine Model of Facioscapulohumeral Muscular Dystrophy. Molecular & Cellular Proteomics, 24 (7). ISSN 1535-9476

Preview

Text Proteomic Profiling Uncovers Sexual Dimorphism in the Muscle Response to Wheel Running Exercise in the FLExDUX4 Murine Model.pdf - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (36MB) | Preview

Abstract

FLExDUX4 is a murine experimental model of facioscapulohumeral muscular dystrophy (FSHD) characterized by chronic, low levels of leaky expression of the human full-length double homeobox 4 gene (DUX4-fl). FLExDUX4 mice exhibit mild pathologies and functional deficits similar to people affected by FSHD. Proteomic studies in FSHD could offer new insights into disease mechanisms underpinned by posttranscriptional processes. We used mass spectrometry–based proteomics to quantify the abundance of 1322 proteins in triceps brachii muscle, encompassing both male and female mice in control and free voluntary wheel running in wildtype (n = 3) and FLExDUX4 (n = 3) genotypes. We report the triceps brachii proteome of FLExDUX4 mice recapitulates key skeletal muscle clinical characteristics of human FSHD, including alterations to mitochondria, RNA metabolism, oxidative stress, and apoptosis. RNA-binding proteins exhibit a sex-specific difference in FLExDUX4 mice. Sexual dimorphism of mitochondrial protein adaptation to exercise was uncovered specifically in FLExDUX4 mice, where females increased, but males decreased mitochondrial proteins after 6-weeks of voluntary wheel running. Our results highlight the importance of identifying sex-specific diagnostic biomarkers to enable more reliable monitoring of FSHD therapeutic targets. Our data provide a resource for the FSHD research community to explore the burgeoning aspect of sexual dimorphism in FSHD.

Item Type:	Article
Uncontrolled Keywords:	DUX4; FSHD; RNA-binding proteins; apoptosis; exercise; mitochondria; oxidative stress; proteomics; skeletal muscle; Animals; Muscular Dystrophy, Facioscapulohumeral; Male; Female; Proteomics; Disease Models, Animal; Muscle, Skeletal; Mice; Sex Characteristics; Physical Conditioning, Animal; Proteome; Homeodomain Proteins; Humans; RNA-Binding Proteins; 3101 Biochemistry and Cell Biology; 32 Biomedical and Clinical Sciences; 31 Biological Sciences; 42 Health Sciences; 4207 Sports Science and Exercise; Genetics; Muscular Dystrophy; Facioscapulohumeral Muscular Dystrophy; Biotechnology; Rare Diseases; 2.1 Biological and endogenous factors; Musculoskeletal; Animals; Muscular Dystrophy, Facioscapulohumeral; Male; Female; Proteomics; Disease Models, Animal; Muscle, Skeletal; Mice; Sex Characteristics; Physical Conditioning, Animal; Proteome; Homeodomain Proteins; Humans; RNA-Binding Proteins; Biochemistry & Molecular Biology
Subjects:	R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions:	Sport and Exercise Sciences
Publisher:	Elsevier
Date of acceptance:	5 June 2025
Date of first compliant Open Access:	28 August 2025
Date Deposited:	28 Aug 2025 14:31
Last Modified:	28 Aug 2025 14:45
DOI or ID number:	10.1016/j.mcpro.2025.101013
URI:	https://researchonline.ljmu.ac.uk/id/eprint/27013

View Item