The team from Sanford Burnham Prebys Medical Discovery Institute landed on a previously unknown step in muscle regeneration driven by stem cells. Most of the time, muscle stem cells are in a resting state and need to be “woken up” to be able to create new muscle fibers, said Lorenzo Puri, M.D., Ph.D., a professor in SBP’s Development, Aging and Regeneration program.
Resting muscle stem cells do not express MyoD, a protein that plays a role in muscle differentiation, because they want to keep their “stemness,” Puri said in an interview with FierceBiotechResearch. When they wake up, they begin to express the protein as they commit to becoming a specific type of muscle.
However, as humans age, muscle stem cells become senescent, a permanently inactive state from which they cannot be roused.
Using mouse models and human fibroblasts — cells that produce collagen and other fibers — Puri’s team found that old muscle stem cells spontaneously trigger a DNA damage response (DDR). The normal DNA damage pathway repairs the DNA and then the signaling terminates, Puri said. However, in the case of old muscle stem cells, there is nothing to repair and the signal persists.
The study, published in Genes & Development, showed that senescence-driven DDR blocks the activity of MyoD and stops the muscle stem cells from differentiating.
The team landed on experimental strategies to get senescent cells to activate muscle generation. But forcing old muscle cells to generate new ones is potentially detrimental; it could lead to the formation of muscle that carries genetic abnormalities or is not fully functional.
While the discovery may not lead to the rejuvenation of muscles for the aging, it could result in ways to make the decline in muscle function more gradual, Puri explained: “There is no way to have an 80-year-old man or woman [regain] the muscle of his or her youth. But we can preserve as much as possible their locomotion and metabolic function, to age in as healthy a way as possible.”
As for patients with muscular dystrophies, who experience a sort of “accelerated aging” of their muscle tissue, Puri feels there is “more room for intervention.” The team is trying to unpack the relationship between these patients’ lack of the dystrophin protein and the ability of MyoD to activate stem cells.
REFERENCE: Fierce Biotech; 01 MAY 2017; Amirah Al Idrus