Scientists at the Sanford Burnham Prebys Medical Discovery Institute have uncovered previously unknown stem cell-mediated steps in muscle regeneration. The findings were published in the journal Genes and Development. The new insights into age-related muscle degeneration will also help researchers studying muscular dystrophies.
Muscle Formation in Adults
In adults, myogenesis or the formation of skeletal muscles is mediated by muscle stem cells (MuSCs). These cells remain a quiescent state and must be activated for new muscle fibers to form. In aging humans, MuSCs go into a permanent state of inactivity known as senescence. They are then unable to become active and generate muscle. Scientists have been trying to discover ways and pharmacologic agents to provoke senescent MuSCs to become active, replicate, and proceed with myogenesis. The hope is that this approach will allow doctors to build muscle in aging individuals and patients with muscular dystrophies.
New Insights into Age-Related Muscle Degeneration
The research team at SBP wanted to discover what molecular determinants cause muscle stem cells to go into a state of irreversible senescence. Experiments were conducted in mouse models with human fibroblasts. The scientists found that there is spontaneous activation of DNA damage in aging MuSCs, even in the absence of toxic agents. This DNA damage response activates the checkpoints that prevent stem cells from replicating.
Professor Lorenzo Puri, M.D., of the Development, Aging, and Regeneration Program explains that the study found MuSC differentiation is disabled by activation of a gene program in the muscles mediated through MyoD.
While the scientists were successful in encouraging senescent stem cells to become active and proceed with myogenesis, they also discovered that muscle fibers formed from aging MuSCs are prone to genomic abnormalities.
Muscle Regeneration in Aging Individuals
Muscle function has a considerable impact on the quality of life and lifespan of aging individuals. Given this, research is focused on better understanding the pathways that lead to progressive muscle stem cell impairment. The goal is to develop target pharmacological therapies to improve muscle formation in aging individuals and patients with muscle pathologies. While the findings are promising, they are also a warning that overenthusiastic strategies to rejuvenate muscles through forced regeneration may come at a trade-off where the new muscle fibers may not have optimal functional and genomic integrity.