Radiation induces long-term muscle fibrosis and promotes a fibrotic phenotype in fibro-adipogenic progenitors

Nicolas Collao; Donna D'Souza; Laura Messeiller; Evan Pilon; Jessica Lloyd; Jillian Larkin; Matthew Ngu; Alexanne Cuillerier; Alexander E Green; Keir J Menzies; Yan Burelle; Michael De Lisio

doi:10.1002/jcsm.13320

Radiation induces long-term muscle fibrosis and promotes a fibrotic phenotype in fibro-adipogenic progenitors

J Cachexia Sarcopenia Muscle. 2023 Oct;14(5):2335-2349. doi: 10.1002/jcsm.13320. Epub 2023 Sep 6.

Authors

Nicolas Collao^{1

2}, Donna D'Souza¹, Laura Messeiller¹, Evan Pilon¹, Jessica Lloyd¹, Jillian Larkin¹, Matthew Ngu¹, Alexanne Cuillerier^{3

4}, Alexander E Green^{2

3

4}, Keir J Menzies^{2

3

4}, Yan Burelle³, Michael De Lisio^{1

2

5}

Affiliations

¹ School of Human Kinetics, Faculty of Health Science, University of Ottawa, Ottawa, Canada.
² Éric Poulin Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Canada.
³ Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada.
⁵ Department of Cellular and Molecular Medicine, Regenerative Medicine Program, University of Ottawa, Ottawa, Canada.

Abstract

Background: Radiation-induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation-induced muscle pathology has not previously been explored.

Methods: Four-week-old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non-IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post-IR (long-term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed.

Results: Juvenile radiation exposure resulted in smaller myofibre cross-sectional area, particularly in type I and IIA myofibres (P < 0.05) and reduced the proportion of type I myofibres (P < 0.05). Skeletal muscle fibrosis (P < 0.05) was evident at 56 days post-IR. The IR-limb had fewer endothelial cells (P < 0.05) and fibro-adipogenic progenitors (FAPs) (P < 0.05) at 56 days post-IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR-limb (P < 0.05). IR induced FAP senescence (P < 0.05), increased their fibrogenic differentiation (P < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (P < 0.05) and fusion (P < 0.05).

Conclusions: Our study suggests that following juvenile radiation exposure, FAPs contribute to long-term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP-targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.

Keywords: Atrophy; Differentiation; Extracellular matrix; Mesenchymal progenitors; Metabolism; Myofibroblast; Skeletal muscle.

Abstract

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