Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD

Abstract

Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD.

Cellular interactions and microenvironment dynamics in skeletal muscle regeneration and disease

“…Furthermore, it has been recently reported that targeting the TGF-β signaling in D2. mdx mice reduce muscle degeneration, calcification and fibrosis by blocking FAP accumulation ( Mázala et al, 2023 ). Similarly, inhibition of Rho-kinase, which is highly expressed in dystrophic muscles ( Zhao et al, 2003 ) reduces FAP PDGF-AA expression, improves muscle function, and reduces fibrosis ( Fernández-Simón et al, 2022 ).…”

“…While TNF is responsible for efficient FAP clearance, the subsequent wave of TGF-β1 blocks the pro-apoptotic effects of TNF and ensures an efficient tissue regeneration ( Lemos et al, 2015 ). Indeed, in dystrophic muscle environments, where a large subset of MPs expresses both TNF and TGF-β1, this ordered transition is disrupted and the muscle presents higher number of FAPs that is correlated with increased fibrosis ( Lemos et al, 2015 ), which also results in a poor regenerative myogenesis and greater muscle degeneration ( Mázala et al, 2023 ). Additionally, in dystrophic muscles dysregulated MPs secrete higher levels of growth factors and latent TGF-β1 that is subsequently activated by FAP-secreted enzymes, further promoting FAPs proliferation and ECM component release ( Juban et al, 2018 ; Wang et al, 2023 ).…”