The role of PDIA3 in myogenesis during muscle regeneration

Beta 3 (β3) integrin plays an important role in the initiation of myogenesis in adult muscle. Protein disulfide isomerases (PDIs) can activate β3 integrin in various cells to promote cell migration, adhesion and fusion. However, the effect of PDIs on myogenesis during muscle regeneration has not been elucidated. Here, we report that PDIA3 expression is induced in regenerating myofibers. The inhibition of PDIA3 in muscle injuries in mice disrupts myoblast differentiation, impairs muscle regeneration, and ultimately aggravates muscle damage. Moreover, PDIA3 expression is upregulated and observed on the cell surfaces of myoblasts during differentiation and fusion. The inhibition of extracellular PDIA3 with an anti-PDIA3 monoclonal antibody attenuates β3 integrin/AKT/mTOR signal activity, inhibits myoblast differentiation, and blocks the fusion of myoblasts. Thus, PDIA3 may be a mediator of myoblast differentiation and fusion during muscle regeneration. A regulatory protein secreted into the extracellular medium helps promote formation of new skeletal muscle tissue after injury. This regenerative process is enabled by muscle cell progenitors called satellite cells, which respond to damage by developing into myoblasts that subsequently fuse into muscle fibers. Researchers led by Xi Peng of the Third Military Medical University in Chongqing, China, have identified the protein PDIA3 as an important intermediary in this process. After chemically inducing muscle damage in mice, the researchers noted that tissue regeneration was associated with a sharp increase in PDIA3 expression. They subsequently linked PDIA3 with activation of a signaling pathway that drives muscle fiber formation and fusion, and demonstrated that inhibition of this protein impeded healing. PDIA3 was not strongly expressed in satellite cells, indicating that it acts relatively late in the maturation process.