RUNX1-Mediated Hypoxic Signaling Impairs Myogenesis and Promotes Fibrosis in Myopathies.

Compromised myogenic repair with enhanced fibrosis is common in myopathies, including Wooden Breast (WB) myopathy in broilers, but the underlying mechanism of their co-occurrence remains elusive. Using WB myopathy as a model, we investigated the common pathological origins of these co-occurring features. Our single-nucleus RNA sequencing results showed enhanced oxidative stress and profibrotic remodeling of myofibers, increased proliferation but decreased differentiation of satellite cells (SCs), and aggravated differentiation of fibroblasts (FBs) in WB samples. Differential gene expression and pseudotime trajectory analysis further identified RUNX1 as a key regulator for both SCs and FBs, which was further supported by gene functional studies in respective cell culture models. Moreover, reduced blood flow and oxygen supply may indicate a hypoxic state in WB muscle, which was associated with enhanced RUNX1 expression. Consistently, coordinately enhanced HIF1A and RUNX1 expressions were found in differentiated FBs of human muscles and in muscles with diseases. Collectively, our study found that hypoxia-associated upregulation of RUNX1 disrupted the myogenic progression of SCs and exacerbated fibrotic differentiation of FBs, contributing to pathological degeneration in myopathies. Targeting RUNX1 may therefore represent a potential therapeutic strategy for prevention and treatment, which warrants future in vivo investigations.