Researchers at Sanford Burnham Prebys Medical Discovery Company (SBP) have identified a previously unrecognized step in originate cell-mediated muscle regeneration. The study, published in Genes and Development , provides new insights for the molecular mechanisms that impair muscle stem cells (MuSCs) during the age-associated decline in muscle function that usually occurs in geriatric individuals. It also provides further regarding the connection between accelerated MuSC aging and muscular dystrophies.
“In adult skeletal muscle mass, the process of generating muscle — myogenesis — depends on triggering MuSCs that are in a resting, or quiescent, state. Even as we age, our MuSCs transition to a permanently inactive condition called senescence, from which they can’t be ‘woken up’ to create new muscle fibers, ” says Lorenzo Puri, Mirielle. D., Ph. D., professor in the Development, Aging plus Regeneration Program at SBP.
“If we’re able to encourage senescent MuSCs to start replicating and advance by means of myogenesis — perhaps through pharmacological interventions — we might have a way to help build muscle in patients that require it, ” adds Puri.
The goal of the research was to define the molecular determinants that result in irreversible MuSC senescence. Using a combination of a mouse design and human fibroblasts, the team found that the cause old MuSCs can’t be activated to generate muscle cells is they spontaneously activate a DNA damage response (DDR) during the absence of exposure to exogenous genotoxic agents. This senescence-associated DDR chronically turns on the machinery needed to repair splits and errors in DNA, and activate cell routine checkpoints, which inhibit cells from dividing.
“In our study, we found that the senescence-associated DDR prevents MUSCs from differentiating by disabling MyoD-mediated service of the muscle gene program, ” explains Puri. “We also learned that a prerequisite for activating the muscles gene program is progression into the cell cycle, a procedure that is irreversibly inhibited in senescent cells. ”
“We did identify experimental strategies to get senescent cells to move through the cell cycle and activate myogenesis, which is a promising result. However , we also discovered that enforcing old MuSCs to form new muscles might lead to the development of myofibers with nuclear abnormalities resulting from genomic modifications generated during aging. ”
“Given the particular tremendous impact that decline in muscle function is wearing aging and lifespan, research that elucidates pathways plus networks that contribute to the progressive impairment of MuSCs — such as that reported here — may lead to focused pharmacological interventions that improve human health, ” Puri notes. “However, the findings from this study should alert against overenthusiasm for strategies aimed at rejuvenating muscle associated with elderly individuals by enforcing the regeneration process, because they might carry a sort of trade-off at the expense of the genomic and possibly functional integrity of the newly formed muscles. ”
Materials provided by Sanford-Burnham Prebys Medical Discovery Institute . Notice: Content may be edited for style and length.