Evidence for Cross-Linking to Impair Muscle Stem Cells

Researchers here provide a little evidence to suggest that increasing stiffness in muscle extracellular matrix, caused in part by growth in the level of persistent cross-links, explains some of the age-related decline in stem cell activity in that tissue. Removal of cross-links, with the primary target being those involving the advanced glycation endproduct glucosepane, is one of the rejuvenation treatments presently under development within the SENS Research Foundation network of scientists. I expect researchers to ultimately find that the age-related decline in stem cell activity - and all of the signaling involved in that decline - has evolved as a response to levels of molecular damage, rather than as an independent genetic program. Broadly repairing that damage should therefore do a lot to restore stem cell activity, though the stem cells' inherent damage will still have to be addressed as well.

Skeletal muscle aging is associated with a decreased regenerative potential due to the loss of function of endogenous stem cells or myogenic progenitor cells (MPCs). Aged skeletal muscle is characterized by the deposition of extracellular matrix (ECM), which in turn influences the biomechanical properties of myofibers by increasing their stiffness. Since the stiffness of the MPC microenvironment directly impacts MPC function, we hypothesized that the increase in muscle stiffness that occurs with aging impairs the behavior of MPCs, ultimately leading to a decrease in regenerative potential.

We showed that freshly isolated aged myofibers contain fewer MPCs, especially quiescent satellite cells, than adult myofibers. These results were comparable to those of other studies showing that the relative number of satellite cells decreases with age, pointing to a lower rate of self-renewal or to asymmetrical division. We recapitulated the MPC behavior observed on myofibers from adult and aged muscles using stiffness-tunable hydrogels and observed that there was a higher proportion of differentiating MPCs in aged damaged myofibers (18 kPa) than in adult damaged myofibers (2 kPa). This is consistent with the results obtained with MPCs grown on the 2 and 18 kPa hydrogels and indicated that there is a more committed MPC phenotype in aged myofibers. It is possible that an increase in the stiffness to 2 kPa of adult damaged myofibers is beneficial for the activation/proliferation of MPCs. On the other hand, an increase in the stiffness to 18 kPa, as observed in damaged aged myofibers, would be deleterious for the proliferation of MPCs but would favor differentiation. This may be one explanation for the decline in the regenerative capacity of aged skeletal muscle.

A growing body of evidence suggests that the stem cell niche serves as an environment in which stem cells respond to extrinsic stimuli associated with muscle growth and repair and that the mechanisms involved are negatively regulated by aging. As we showed, when MPCs are dissociated from their niche, the proliferation and differentiation potentials of MPCs from aged mice are similar to those of MPCs from adult mice, which lends support to the importance of the MPC niche. The composition of the ECM affects the mechanical properties of the tissue microenvironment, which in turn influences the activity of stem cells. Given that the ECM plays a major role in the increase in stiffness that occurs with age, some authors have suggested that there is a correlation between the increase in collagen deposition and the increase in muscle stiffness, with advanced glycation end-products (AGEs) playing a major role in glycation and collagen reticulation. Changes in the composition of the ECM during aging would thus provide regulatory cues to stem cells, modulating their quiescence, activation, differentiation, and/or self-renewal. In the present study, we confirmed that the increase in collagen deposition in the muscles of aged mice is correlated with an increase in hydroxyproline and AGE levels. These results reinforce the notion that the ECM undergoes qualitative and quantitative modifications with aging that would alter the myofiber repair process.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546553/


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