Extracellular Matrix Protein Tenascin-C is Important to Muscle Stem Cell Function, But Declines with Age
The aging of the extracellular matrix is not as well studied as is the case for cell biochemistry. There are likely many important changes that take place in the extracellular matrix over a lifetime that meaningfully affect cell function in aged tissues, but have yet to be discovered and understood. One example is outlined here, a matrix protein that declines with age but seems necessary to maintain the normal function of muscle stem cells. Declining muscle stem cell function is one of the important contributions to the characteristic loss of muscle mass and strength that occurs with age.
Skeletal muscle regeneration occurs through the finely timed activation of resident muscle stem cells (MuSC). Following injury, MuSC exit quiescence, undergo myogenic commitment, and regenerate the muscle. This process is coordinated by tissue microenvironment cues, however the underlying mechanisms regulating MuSC function are still poorly understood.
Here, we demonstrate that the extracellular matrix protein Tenascin-C (TnC) promotes MuSC self-renewal and function. Mice lacking TnC exhibit reduced number of MuSC, and defects in MuSC self-renewal, myogenic commitment, and repair. We show that fibro-adipogenic progenitors are the primary cellular source of TnC during regeneration, and that MuSC respond through the surface receptor Annexin A2. We further demonstrate that TnC declines during aging, leading to impaired MuSC function. Aged MuSC exposed to soluble TnC show a rescued ability to both migrate and self-renew in vitro.
Overall, our results highlight the pivotal role of TnC during muscle repair in healthy and aging muscle.