Collagen Crosslinking Does Not Dictate Stiffness in a Transgenic Mouse Model of Skeletal Muscle Fibrosis

Skeletal muscle fibrosis is marked by increases in tissue stiffness and collagen content. However, only a very weak correlation exists between collagen content and stiffness in skeletal muscle. Recently, it has been hypothesized that collagen crosslinking explains tissue stiffness in fibrotic skeletal muscle. Therefore, we addressed this hypothesis by correlating tissue stiffness with lysyl-pyridinoline, hydroxylysyl-pyridinoline, and pentosidine collagen crosslinks. Stepwise regression revealed that, separate or together, collagen crosslinks did not correlate with tissue stiffness. Our result demonstrates that increased tissue stiffness in skeletal muscle fibrosis is not simply explained by increased collagen crosslinks and/or collagen crosslink density. We suggest that collagen organization may affect tissue stiffness. Alternatively, changes in other extracellular matrix components or specific structural geometry could dictate tissue stiffness.