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Evaluation of Injury-induced Senescence and In Vivo Reprogramming in the Skeletal Muscle
Published on: October 26, 2017
DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle
Lucia Latella1,2, Alessandra Dall'Agnese3,4, Francesca Sesillo Boscolo3,4
1Epigenetics and Regenerative Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy.
Abstract:
The molecular determinants of muscle progenitor impairment to regenerate aged muscles are currently unclear. We show that, in a mouse model of replicative senescence, decline in muscle satellite cell-mediated regeneration coincides with activation of DNA damage response (DDR) and impaired ability to differentiate into myotubes. Inhibition of DDR restored satellite cell differentiation ability. Moreover, in replicative human senescent fibroblasts, DDR precluded MYOD-mediated activation of the myogenic program. A DDR-resistant MYOD mutant 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. Of note, we found that cell cycle progression is necessary for the DDR-resistant MYOD mutant to reverse senescence-mediated inhibition of the myogenic program. These data provide the first evidence of DDR-mediated functional antagonism between senescence and MYOD-activated gene expression and indicate a previously unrecognized requirement of cell cycle progression for the activation of the myogenic program.
Insights
Muscle regeneration declines with aging due to DNA damage response (DDR) activation, which impairs satellite cell differentiation. Inhibiting DDR or promoting cell cycle progression restores muscle regeneration in aged and senescent cells.
Area of Science:
- Muscle regeneration
- Cellular senescence
- DNA damage response
Background:
- Muscle progenitor impairment hinders aged muscle regeneration.
- Molecular mechanisms underlying this decline are not fully understood.
Purpose of the Study:
- Investigate the role of DNA damage response (DDR) in age-related muscle regeneration impairment.
- Determine if DDR inhibition or cell cycle modulation can restore myogenic potential in senescent cells.
Main Methods:
- Utilized a mouse model of replicative senescence.
- Examined DNA damage response (DDR) activation and satellite cell differentiation.
- Assessed MYOD-mediated myogenic program activation in human senescent fibroblasts.
- Employed a DDR-resistant MYOD mutant and evaluated cell cycle progression.
Main Results:
- In senescent mice, DDR activation correlated with reduced satellite cell regeneration and differentiation.
- Inhibition of DDR restored satellite cell differentiation capacity.
- In human senescent fibroblasts, DDR blocked MYOD-driven myogenic program activation.
- A DDR-resistant MYOD mutant restored the myogenic program, contingent on cell cycle progression.
Conclusions:
- DNA damage response (DDR) functionally antagonizes senescence and MYOD-driven gene expression in muscle regeneration.
- Cell cycle progression is essential for reversing senescence-induced inhibition of the myogenic program.
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