A Transcriptomic Map of Age-Related Loss of Muscle Regenerative Capacity
Researchers here produce a map of transcription in muscle regeneration in mice of various ages, separated by cell type and time following muscle injury. The results are interesting, and show that the participation of the immune system in regeneration becomes dysregulated in older animals. Muscle stem cell function also declines, as might be expected. Restoring the aged immune system and aged stem cell populations are both sizable challenges facing those intent on developing the first rejuvenation therapies, but clearly very important.
The immune, stromal, and myogenic cells found in skeletal muscle contribute to muscle maintenance and regeneration by regulating muscle stem cell (MuSC) quiescence, proliferation, and differentiation. It has been shown that an imbalance in immune cell populations during injury response can disrupt proper muscle repair. To investigate this, we compared the change in cell-type abundances over our regeneration time course between young, old, and geriatric muscles. As expected, neutrophils are one of the first immune cell types to peak in abundance. We also observe monocyte and macrophage populations that express pro-inflammatory markers like Ccr2 and patrolling markers like Ctsa responding soon after injury (days 1-2) when we expect the muscle environment to be enriched with pro-inflammatory cytokines. Monocytes and macrophages that express pro-inflammatory markers clear cellular debris and promote myogenic cell proliferation. There should be a shift to monocytes and macrophages that express anti-inflammatory marker C1qa at days 4-7 following injury.
We do broadly observe a shift from monocytes and macrophages that express pro-inflammatory markers to anti-inflammatory markers, but there are significant differences by age. This difference in monocyte and macrophage dynamics could explain the age-related decline in muscle repair because if macrophages do not clear cellular debris or promote myogenic cell proliferation and differentiation, the muscle remains inflamed and there are repeated cycles of necrosis and regeneration. The damaged myofibers are then replaced with adipose tissue, fibrotic tissue or bone, instead of new myofibers. In addition to age-specific differences in the dynamics of the monocyte and macrophage populations, we observe age-specific differences in the T cell dynamics. There is miscoordination of the T cell response, which in turn could impact the ability of aged muscle to repair itself.
One factor that has been shown to contribute to the reduced functionality of MuSCs in aged tissues is the establishment of senescent MuSCs. Our data is supportive of a senescent-like MuSC and progenitor population that is more abundant in the geriatric mice, suggesting stalled stem cell self-renewal in mouse muscle aging. Together, these observations point to a transitory senescent-like cell population that is abundant at the self-renewing MuSC stage during regeneration across all ages of mice. This population of senescent-like MuSCs increases within the injury zone and in older mice, suggesting that a stalled stem cell self-renewal state underlies the regenerative dysfunction in mouse aging.