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New insights on triggering muscle formation

Research uncovers molecular reasons why aged muscle loses the ability to regenerate

Date:
April 25, 2017
Source:
Sanford-Burnham Prebys Medical Discovery Institute
Summary:
A previously unrecognized step in stem cell-mediated muscle regeneration has now been discovered by scientists. The study provides new insights into the molecular mechanisms that impair muscle stem cells during the age-associated decline in muscle function, and into the connection between accelerated muscle aging and muscular dystrophies.
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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 Lorenzo Puri, M.D., Ph.D., professor in the Development, Aging and Regeneration Program at SBP.

"If we could encourage senescent MuSCs to start replicating and advance through myogenesis -- perhaps through pharmacological interventions -- we may have a way to help build muscle in patients that need it," adds Puri.

The goal of the study was to define the molecular determinants that lead to irreversible MuSC senescence. Using a combination of a mouse model and human fibroblasts, the team found that the reason old MuSCs can't be activated to generate muscle cells is that they 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 cell cycle checkpoints, which inhibit cells from dividing.

"In our study, we found that the senescence-associated DDR prevents MUSCs from differentiating by disabling MyoD-mediated activation of the muscle gene program," explains Puri. "We also learned that a prerequisite for activating the muscle gene program is progression into the cell cycle, a process 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 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," Puri notes. "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."


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Materials provided by Sanford-Burnham Prebys Medical Discovery Institute. Note: Content may be edited for style and length.


Journal Reference:

  1. Lucia Latella, Alessandra Dall'Agnese, Francesca Boscolo Sesillo, Chiara Nardoni, Marianna Cosentino, Armin Lahm, Alessandra Sacco, Pier Lorenzo Puri. DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes & Development, 2017; 31 (7): 648 DOI: 10.1101/gad.293266.116

Cite This Page:

Sanford-Burnham Prebys Medical Discovery Institute. "New insights on triggering muscle formation: Research uncovers molecular reasons why aged muscle loses the ability to regenerate." ScienceDaily. ScienceDaily, 25 April 2017. <www.sciencedaily.com/releases/2017/04/170425171655.htm>.
Sanford-Burnham Prebys Medical Discovery Institute. (2017, April 25). New insights on triggering muscle formation: Research uncovers molecular reasons why aged muscle loses the ability to regenerate. ScienceDaily. Retrieved May 27, 2017 from www.sciencedaily.com/releases/2017/04/170425171655.htm
Sanford-Burnham Prebys Medical Discovery Institute. "New insights on triggering muscle formation: Research uncovers molecular reasons why aged muscle loses the ability to regenerate." ScienceDaily. www.sciencedaily.com/releases/2017/04/170425171655.htm (accessed May 27, 2017).

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