Facioscapulohumeral Muscular Dystrophy is Associated With Altered Myoblast Proteome Dynamics

Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; D2O) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of “older” less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Treatment with a 2′-O-methoxyethyl modified antisense oligonucleotide targeting exon 3 of the double homeobox 4 (DUX4) transcript tended to reverse mitochondrial protein dysregulation in FSHD myoblasts, indicating the effect on mitochondrial proteins may be a DUX4-dependent mechanism. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD. [Display omitted] •Dynamic profiling of myoblasts from FSHD patients and their unaffected siblings.•Median protein turnover is slower in FSHD myoblasts than their unaffected siblings.•Mitochondrial proteins are more abundant in FSHD myoblasts.•Mitochondrial proteins exhibit a slower protein turnover rate in FSHD myoblasts.•2′-MOE treatment partly reversed the dysregulation of mitochondrial proteins in FSHD. Nishimura et al. used dynamic proteome profiling to uncover new disease mechanisms underpinned by post-transcriptional processes in FSHD. Deuterium oxide (D2O) labeling and peptide mass spectrometry were used to obtain the abundance and turnover rates of proteins in myoblasts from two individuals with FSHD and their unaffected siblings. The results identified that FSHD myoblasts exhibit greater abundance but a slower turnover rate of mitochondrial proteins, which may indicate an accumulation of “older” less viable mitochondrial proteins in FSHD myoblasts.