New Insights into Neuromuscular Contracture Reveals Myotendinous- SMAD4 Signaling Underlies Contracture Formation

Abstract

Neuromuscular contractures (NC) are a prevalent cause of joint deformity in children suffering from neuromuscular disorders or nerve damage, leading to persistent disability. The role of tendon in the development of NC remains poorly understood, with current treatments predominantly targeting muscle. Here, we establish a surgical model of NC in the hindlimb that recapitulates functional deformity and transcriptomic changes observed in human disease. Our findings indicate that in NC, tendons dramatically elongate, undergoing changes in matrix and structural composition that reduce tensile stiffness. Contrary to expectations, we find that tendon elongation was principally driven by increased myotendon infiltration into muscle which restricted muscle elongation contributing to NC. Using lineage tracing, we show that myotendon elongation was due to increased infiltration of intrinsically derived tenocytes. Transcriptional profiling revealed BMP signaling as a key factor in myotendon elongation, corroborated by elevated myotendinous Smad4 activity in both our mouse model and in human NC tissues. Crucially, administration of a small molecule inhibitor of BMP-mediated Smad4 signaling not only restored joint mobility but also prevented myotendon elongation. These insights establish of a clinically relevant mouse model of NC and unveil a novel role for myotendon elongation in NC progression. Excitingly, our results suggest that targeting myotendon signaling could represent a new direction for tendon-focused therapies in NC management.