LA JOLLA, Calif.—Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a previously unrecognized step in stem cell-mediated muscle regeneration. The study, published in Genes and Development, provides new insights on the molecular mechanisms that impair muscle stem cells (MuSCs) during the age-associated decline in muscle function that typically occurs in geriatric individuals. It also provides further insight into the connection between accelerated MuSC aging and muscular dystrophies.
“In adult skeletal muscle, the process of generating muscle myogenesis depends on activating MuSCs that are in a resting, or quiescent, state. As we age, our MuSCs transition to a permanently inactive state called senescence, from which they can’t be ‘woken up’ to form new muscle fibers,” says Dr. Lorenzo Puri, professor in the Development, Aging and Regeneration Program at SBP.
The SBP team sought to define the molecular determinants that lead to this currently irreversible MuSC senescence in hopes of identifying potential targets for strategies that enable “healthy” regeneration of skeletal muscles. Using a combination of a mouse model and human fibroblasts, the research suggested that aged MuSCs spontaneously activate a DNA damage response (DDR) even in the absence of exposure to exogenous genotoxic agents. This senescence-associated DDR chronically turns on the machinery needed to repair breaks and errors in DNA, and activate the so-called “cell cycle checkpoints” that inhibit cells from dividing. The team found that once adult stem cells undergo senescence, they are “locked” into a state that prevents their ability to regenerate their target tissue, in what appears to be a protective mechanism.
“Our data suggest that this is a sort of protection against the accretion of senescent nuclei to multinucleated tissues, such as skeletal muscles, which could eventually spread senescence-related mutations and thereby increase genomic instability. Essentially, the antagonism between senescence and muscle stem cell regeneration ability seems to be a sort of 'trade-off' by which aged organisms protect against the formation of genetically unstable and functionally impaired skeletal muscles,” according to Puri. While this seems a reasonable hypothesis for multinucleated tissues, Puri believes it is hard to say whether this hypothesis can also apply to other tissues/organs.
The next step is to further understand the relationship between the recovery of the cell cycle in senescent muscle stem cells, their ability to differentiate into myofibers and the maintenance of the genomic integrity. A DDR-resistant MYOD protein (activated in response to exercise or muscle tissue damage) could overcome this barrier by resuming cell cycle progression. Likewise, DDR inhibition could also restore MYOD's ability to activate the myogenic program in human senescent fibroblasts.
The research provides a window into potential new treatments to enable or promote healthy regeneration of senescent skeletal muscles. Puri stresses, however, that novel anti-aging therapies were not the focus of this research. “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 formation of myofibers with nuclear abnormalities resulting from genomic alterations generated during aging. Given the tremendous impact that decline in muscle function has on aging and lifespan, research that elucidates pathways and networks that contribute to the progressive impairment of MuSCs—such as that reported here—may lead to targeted pharmacological interventions that improve human health.
“However, the findings from this study should warn against overenthusiasm for strategies aimed at rejuvenating muscle of elderly individuals by enforcing the regeneration process, as they might carry a sort of trade-off at the expense of the genomic and possibly functional integrity of the newly formed muscles. The point [of the paper we published] was to caution against the current excitement toward strategies that propose to promote muscle regeneration in aged individuals.”