“The Social Network” and Muscular Dystrophies: The Lesson Learnt about the Niche Environment as a Target for Therapeutic Strategies

Abstract

<jats:p>The muscle stem cells niche is essential in neuromuscular disorders. Muscle injury and myofiber death are the main triggers of muscle regeneration via satellite cell activation. However, in degenerative diseases such as muscular dystrophy, regeneration still keep elusive. In these pathologies, stem cell loss occurs over time, and missing signals limiting damaged tissue from activating the regenerative process can be envisaged. It is unclear what comes first: the lack of regeneration due to satellite cell defects, their pool exhaustion for degeneration/regeneration cycles, or the inhibitory mechanisms caused by muscle damage and fibrosis mediators. Herein, Duchenne muscular dystrophy has been taken as a paradigm, as several drugs have been tested at the preclinical and clinical levels, targeting secondary events in the complex pathogenesis derived from lack of dystrophin. We focused on the crucial roles that pro-inflammatory and pro-fibrotic cytokines play in triggering muscle necrosis after damage and stimulating satellite cell activation and self-renewal, along with growth and mechanical factors. These processes contribute to regeneration and niche maintenance. We review the main effects of drugs on regeneration biomarkers to assess whether targeting pathogenic events can help to protect niche homeostasis and enhance regeneration efficiency other than protecting newly formed fibers from further damage.</jats:p>

Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche

“…These include immune cells and fibroblasts which play critical roles in all the stages of muscle repair [51]. Figure 2 summarises the relationship between the different cell type influencing muscle growth and repair in inflammatory conditions such as rheumatoid arthritis [34,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65].…”

Platelet Derived Growth Factor-AA Correlates With Muscle Function Tests and Quantitative Muscle Magnetic Resonance in Dystrophinopathies

“…The process of muscle fibrosis in patients with muscular dystrophies is highly complex and not completely understood (34). It is known that chronic muscle degeneration leads to persistent inflammatory infiltration, muscle necrosis and activation of fibroadipogenic progenitor cells (FAPs) and fibroblasts, which release proteins of the extracellular matrix such as collagen-I, leading to the expansion of fibrotic tissue (34)(35)(36). The PDGF family in general and PDGF-AA in particular play an important role in this process (22, 37).…”

Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis

“…While most of these strategies are obviously focused on muscle cells, which bear the genetic defect, it is now clear in the field that we should also take into account the cellular environment. Indeed, several studies demonstrated the importance of non-muscle cells in the progression of MDs, particularly MPs 28,[40][41][42][43] . In this study, we demonstrated that the expression of transcription factor Nfix induces pro-fibrotic features in MPs in a context of chronic muscle injury.…”