Platelet-Derived Growth Factor BB Influences Muscle Regeneration in Duchenne Muscle Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration.

Platelet releasate promotes skeletal myogenesis by increasing muscle stem cell commitment to differentiation and accelerates muscle regeneration following acute injury

“…Previous research data suggest that VEGF is important for myogenin expression as well as myoblast and myotube number . Moreover, addition of PDGF‐BB to myoblasts inhibits differentiation . Of note, the myotube fusion index did not significantly differ amongst groups, indicating proliferation factors may be necessary for proper differentiation capacity and that lower total nuclei number may be accountable for the attenuated differentiation.…”

“…This may possibly be due to a crosstalk with other growth factor receptors present in the releasate such as EGFR when used in high concentrations . This notion is strengthened by previous studies showing that PDGF/VEGF inhibition resulted in diminished myoblast proliferation and recombinant PDGFs improved skeletal muscle recovery after injury …”

Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing

“…In addition, the laminin diversity in different tissue ECMs and the different GF-binding profiles could be associated with regulation of GF contents and functions in specific tissues. For example, PDGF-BB has been reported to enhance muscle regeneration by activating satellite cell proliferation and migration 48 and to protect the myocardium from ischemic injury 49 . Laminin-211 is the most abundant isoform in adult skeletal muscle tissue 50 and is also expressed in the myocardium 51 .…”

Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy

“…The role of PDGF-BB is not so clearly established. Whereas it seems that PDGF-BB could have a role in the fibrosis observed in a number of tissues, several authors suggest that it can also play an important role in muscle regeneration in vivo 41 , 42 .…”