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

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.