HDAC4 myonuclear reprogramming underlies denervation and weakness following musculoskeletal trauma

Muscle weakness following joint injury contributes to substantial functional deficits and disability. The molecular etiology of prolonged muscle atrophy and weakness following knee ligament injury remains undefined, limiting our understanding of the inceptive events underlying poor functional recovery. We studied the muscle transcriptome in men and women in response to ligament injury and surgical reconstruction, revealing substantial injury- and reconstructive surgery-dependent changes, with sustained increases in genes associated with neuromuscular junction remodeling. We identified histone deacetylase 4 (HDAC4) as one of the most upregulated targets in muscle following both injury and reconstruction, and multi-omics integration of HDAC4 ChIP-sequencing and RNA-sequencing revealed a coordinated repression of genes associated with metabolism and contractile function following injury. We further applied single nucleus RNA-sequencing and uncovered aberrant neuromuscular signaling and myonuclear reprogramming. Our multi-omics and single-nucleus transcriptome analyses demonstrate unique myocellular and neuromuscular adaptations that could explain persistent functional deficits following acute musculoskeletal injury.