Overactive PDGFRα and PDGFRβ promote distinct phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving muscle growth.

Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of appropriate experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFRα or PDGFRβ) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote extracellular matrix (ECM) deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. To test this hypothesis, we used a mouse model with inducible overactive PDGFRα or PDGFRβ signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Overactive PDGFRα led to higher collagen deposition, collagen cross linking, and AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared with controls. Overactive PDGFRβ resulted in greater muscle mass and lower fat mass and had higher collagen deposition in female mice compared with controls. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFRα and PDGFRβ signaling. These findings establish PDGFRα and PDGFRβ signaling as distinct regulators of muscle remodeling and establish overactive PDGFRα as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.