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 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.