Muscle Growth and Fibrosis in Neuromuscular Contracture Pathogenesis
We have shown in our mouse model of NBPI that impaired longitudinal growth of denervated muscle contributes to contracture formation. However, we must also consider other potential factors in contracture pathology. Besides impaired growth, we have also found increased tissue fibrosis in denervated muscle, as characterized by an increase in extracellular collagen deposition. The concurrent growth deficits and extracellular matrix (ECM) remodeling in denervated muscle suggests that muscle growth and fibrosis may represent biologically linked processes in contracture formation. This may also explain why prior efforts to inhibit pathways driving impaired growth (myostatin signaling) or fibrosis (TGF-ß signaling) alone do not fully correct contractures.
To gain stronger insights on muscle growth and fibrosis in contracture pathology, we are presently investigating the role of latent transforming growth factor beta 4 (LTBP4), an endogenous inhibitor of both myostatin signaling and TGF-ß signaling. Using our mouse model, we have recently found that genetic loss of Ltbp4 function leads to more severe contractures after NBPI by further impairing longitudinal muscle growth and worsening fibrosis. While still preliminary, these early results reveal a potential role for the interplay between both aberrant muscle growth and abnormal muscle ECM in modulating contractures. Moreover, our findings reveal LTBP4 as a putative master regulator of both these elements of NBPI muscle pathology, thereby identifying a potentially high-yield target for contracture therapy. We have presented these important discoveries at the ORS 2026 Annual Meeting. 1
In addition to the loss of function study, ongoing gain-of-function approaches using our mouse model will also assess whether Ltbp4 overexpression is sufficient to rescue contractures. These complementary experiments will provide more thorough biological and translational insights on muscle growth and fibrosis in contracture pathology, and further elucidate LTBP4 as a potential novel target for contracture therapy. This research is currently funded by the Pediatric Orthopaedic Society of North America.
1. Elucidating the role of LTBP4 in neuromuscular contracture pathogenesis. Dickman S and Crawford C, Symson L, Shay-Winkler K, Goh Q, Cornwall R. ORS 2026 Annual Meeting, Charlotte, NC.
