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Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress.

Publication ,  Journal Article
O'Connor, TN; Kallenbach, JG; Orciuoli, HM; Paris, ND; Bachman, JF; Johnston, CJ; Hernady, E; Williams, JP; Dirksen, RT; Chakkalakal, JV
Published in: Skelet Muscle
April 12, 2022

BACKGROUND: Radiotherapy is commonly used to treat childhood cancers and can have adverse effects on muscle function, but the underlying mechanisms have yet to be fully elucidated. We hypothesized that endurance exercise following radiation treatment would improve skeletal muscle function. METHODS: We utilized the Small Animal Radiation Research Platform (SARRP) to irradiate juvenile male mice with a clinically relevant fractionated dose of 3× (every other day over 5 days) 8.2 Gy X-ray irradiation locally from the knee to footpad region of the right hindlimb. Mice were then singly housed for 1 month in cages equipped with either locked or free-spinning voluntary running wheels. Ex vivo muscle contractile function, RT-qPCR analyses, resting cytosolic and sarcoplasmic reticulum (SR) store Ca2+ levels, mitochondrial reactive oxygen species levels (MitoSOX), and immunohistochemical and biochemical analyses of muscle samples were conducted to assess the muscle pathology and the relative therapeutic impact of voluntary wheel running (VWR). RESULTS: Irradiation reduced fast-twitch extensor digitorum longus (EDL) muscle-specific force by 27% compared to that of non-irradiated mice, while VWR post-irradiation improved muscle-specific force by 37%. Radiation treatment similarly reduced slow-twitch soleus muscle-specific force by 14% compared to that of non-irradiated mice, while VWR post-irradiation improved specific force by 18%. We assessed intracellular Ca2+ regulation, oxidative stress, and mitochondrial homeostasis as potential mechanisms of radiation-induced pathology and exercise-mediated rescue. We found a significant reduction in resting cytosolic Ca2+ concentration following irradiation in sedentary mice. Intriguingly, however, SR Ca2+ store content was increased in myofibers from irradiated mice post-VWR compared to mice that remained sedentary. We observed a 73% elevation in the overall protein oxidization in muscle post-irradiation, while VWR reduced protein nitrosylation by 35% and mitochondrial reactive oxygen species (ROS) production by 50%. Finally, we found that VWR significantly increased the expression of PGC1α at both the transcript and protein levels, consistent with an exercise-dependent increase in mitochondrial biogenesis. CONCLUSIONS: Juvenile irradiation stunted muscle development, disrupted proper Ca2+ handling, damaged mitochondria, and increased oxidative and nitrosative stress, paralleling significant deficits in muscle force production. Exercise mitigated aberrant Ca2+ handling, mitochondrial homeostasis, and increased oxidative and nitrosative stress in a manner that correlated with improved skeletal muscle function after radiation.

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Published In

Skelet Muscle

DOI

EISSN

2044-5040

Publication Date

April 12, 2022

Volume

12

Issue

1

Start / End Page

8

Location

England

Related Subject Headings

  • Sarcoplasmic Reticulum
  • Reactive Oxygen Species
  • Muscle, Skeletal
  • Motor Activity
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Animals
  • 3208 Medical physiology
 

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O’Connor, T. N., Kallenbach, J. G., Orciuoli, H. M., Paris, N. D., Bachman, J. F., Johnston, C. J., … Chakkalakal, J. V. (2022). Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress. Skelet Muscle, 12(1), 8. https://doi.org/10.1186/s13395-022-00291-y
O’Connor, Thomas N., Jacob G. Kallenbach, Haley M. Orciuoli, Nicole D. Paris, John F. Bachman, Carl J. Johnston, Eric Hernady, Jacqueline P. Williams, Robert T. Dirksen, and Joe V. Chakkalakal. “Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress.Skelet Muscle 12, no. 1 (April 12, 2022): 8. https://doi.org/10.1186/s13395-022-00291-y.
O’Connor TN, Kallenbach JG, Orciuoli HM, Paris ND, Bachman JF, Johnston CJ, et al. Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress. Skelet Muscle. 2022 Apr 12;12(1):8.
O’Connor, Thomas N., et al. “Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress.Skelet Muscle, vol. 12, no. 1, Apr. 2022, p. 8. Pubmed, doi:10.1186/s13395-022-00291-y.
O’Connor TN, Kallenbach JG, Orciuoli HM, Paris ND, Bachman JF, Johnston CJ, Hernady E, Williams JP, Dirksen RT, Chakkalakal JV. Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress. Skelet Muscle. 2022 Apr 12;12(1):8.
Journal cover image

Published In

Skelet Muscle

DOI

EISSN

2044-5040

Publication Date

April 12, 2022

Volume

12

Issue

1

Start / End Page

8

Location

England

Related Subject Headings

  • Sarcoplasmic Reticulum
  • Reactive Oxygen Species
  • Muscle, Skeletal
  • Motor Activity
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Animals
  • 3208 Medical physiology