Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy

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 post-transcriptional 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 (VWR) in Wild-type (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 a 6-week of VWR. Our results highlight the importance of identifying sex-specific diagnostic biomarkers to enable more reliable monitoring of FSHD therapeutic targets. Our data provides a resource for the FSHD research community to explore the burgeoning aspect of sexual dimorphism in FSHD. In BriefNishimura et al. conducted proteomic analysis of triceps brachii muscle in the FLExDUX4 murine model of FSHD and verified FLExDUX4 mice recapitulate key skeletal muscle clinical characteristics of human FSHD, including disruptions to the mitochondrial proteome and proteins associated with RNA metabolism, oxidative stress, and apoptosis. RNA-binding proteins and the mitochondrial proteome response to exercise exhibited sexual dimorphism in FLExDUX4 mice. Specifically, females exhibited increases, whereas males exhibited decreases in mitochondrial protein abundance after 6-weeks voluntary wheel running. HighlightsO_LIFLExDUX4 muscle proteome mirrors pathophysiology of FSHD patient myoblasts C_LIO_LIMitochondrial proteins are more abundant in FLExDUX4 as compared to WT mice C_LIO_LISeverity of proteome disruption is greater in male than female mice C_LIO_LIRNA-binding proteins exhibit a sex-specific difference in FLExDUX4 mice C_LIO_LISex-specific mitochondrial proteome response to VWR in FLExDUX4 mice C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/639012v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1bf8a40org.highwire.dtl.DTLVardef@dad2borg.highwire.dtl.DTLVardef@1e402e7org.highwire.dtl.DTLVardef@7aad7c_HPS_FORMAT_FIGEXP M_FIG C_FIG