Exercise attenuates juvenile irradiation-induced skeletal muscle decline by improving calcium handling and decreasing mitochondrial stress.
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2022-09
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Proper skeletal muscle development, maintenance, and function is necessary for movement. Decline in muscle function with age and disease is directly associated with a diminished quality of life. Radiation therapy is commonly used to treat certain forms of childhood cancer based on the cytotoxic effects of radiation on cancerous tissue. However, the adverse effects elicited by radiation are not always constrained to the diseased tissue and can accelerate muscle wasting and decline, which is particularly detrimental to juvenile cancer survivors. Exercise is effective at limiting muscle decline and improving muscle function in various diseases. Thus, we hypothesized 1 mo of voluntary endurance exercise following juvenile radiation treatment will reduce muscle damage and restore functional deficits that occur following radiation. Here, we show that following juvenile radiation, 1 mo of voluntary wheel running significantly improved muscle function in mice by promoting adaptations in intracellular calcium handling, improving mitochondrial turnover and reducing oxidative stress resulting from radiation-induced mitochondrial damage. These findings help guide caregivers in their approach to childhood cancer survivor recovery and have implications for other diseases where similar mechanisms of calcium handling and mitochondrial function are disrupted.
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O'Connor, Thomas N, Jacob G Kallenbach, Joe V Chakkalakal and Robert T Dirksen (2022). Exercise attenuates juvenile irradiation-induced skeletal muscle decline by improving calcium handling and decreasing mitochondrial stress. The Journal of general physiology, 154(9). 10.1085/jgp.2021ecc21 Retrieved from https://hdl.handle.net/10161/25084.
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Joe Chakkalakal
Laboratory of Neuromuscular Development, Regeneration, and Aging
We study the cellular and molecular mechanisms underlying neuromuscular development, regeneration, and aging with an emphasis on understanding stem and progenitor cell fate and function, and stem cell niche biology. We are affiliated with the Departments of Orthopaedic Surgery and Cell Biology as part of the Duke Orthopaedic Cellular, Developmental, and Genome Laboratories within the Duke University School of Medicine.
Aging-related declines in neuromuscular regeneration:
Aging is associated with significant deficiencies in skeletal muscle regeneration. We believe the inhibition of regenerated aged myofiber recovery coupled with interstitial pathological infiltrate and fibrosis are due to impairments in the reconstitution of the neuromuscular junction (NMJ), a specialized site where the synapse between a motor axon terminal and myofiber is located. Current studies include examining the cellular basis for the restoration of NMJs after injury. We are also pursuing mechanisms such as the manipulation of relevant stem and progenitor cell populations that may alter NMJ reconstitution after injury and how they impact myofiber recovery, interstitial pathological infiltrate, and fibrosis.
Postnatal neuromuscular growth and the consequences of pediatric cancer therapies:Neuromuscular impairments are among the aging-related phenotypes observed earlier in pediatric cancer survivors. Early adolescence to adulthood is a period of significant skeletal muscle growth with active stem and progenitor cell activity that is sensitive to pediatric cancer therapies such as radiation and chemotherapy. Current studies involve examining how modulations in the cellular composition of skeletal muscle, the fate of stem and progenitor cell populations, and alterations of the muscle stem cell niche from early adolescence to adulthood impact healthy aging. We are also pursuing strategies to alleviate the near and long term impact of pediatric cancer therapies during this dynamic stage of neuromuscular growth.
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