Weight loss with exercise improves muscle architecture and progenitor cell populations compared to weight loss alone in mice with preneoplastic colorectal lesions

Roubos, Sophia; D’Souza, Donna M.; Hernández-Saavedra, Diego; Xu, Guanying Bianca; Collao, Nicolás; Emmons, Russell; Larkin, Jillian; Lloyd, Jessica; Vanhie, James J; Pan, Yuan; Chen, Hong; Lisio, Michael De

doi:10.1139/apnm-2020-0956

Cited by 3 publications

(4 citation statements)

References 55 publications

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“…In line with previous work, 6 RMS plus therapy did not result in FAP depletion; however, we did observe a trend for fewer FAPs in RMS + Tx‐SED versus CON‐SED. Conversely, we observed significantly more FAPs following RET in both CON and RMS plus therapy, which aligns with previous preclinical models of endurance exercise 15 , 20 , 33 and resistance training studies in humans. 34 Further, we detected more fibrosis in the RMS plus therapy condition, 15 which aligns with our transcriptional analysis that showed an enrichment in genes involved in platelet‐derived growth factor (PDGF) signalling in RMS + Tx‐SED compared to CON‐SED.…”

Section: Discussionsupporting

confidence: 91%

“…An average of 482 ± 22.5 myofibres per mouse were analysed for cross‐sectional area (CSA), fibre‐type proportion and myonuclear domain. Masson's trichrome 15 , 20 and myosin heavy chain (MyHC) 21 staining and analysis were conducted as previously described. The following isotype‐specific anti‐mouse primary antibodies were used: MyHC‐I, IgG‐2b (1:100, Cat# BA‐D5, DSHB), MyHC‐IIA, IgG1 (1:100, Cat# SC‐71, DSHB), MyHC‐IIB, IgM (1:25, Cat# BF‐F3, DSHB), and anti‐laminin, IgG (1:50, Cat# MA1‐06100 Monoclonal Antibody (A5), Thermo Fisher Scientific) with their corresponding secondary antibodies: Alexa Fluor® 647 AffiniPure Goat Anti‐Mouse IgG, Fcγ subclass 2b specific (1:100, Cat# 115‐605‐207, Cedarlane Laboratories), Alexa Fluor® 488 AffiniPure Goat Anti‐Mouse IgG, Fcγ subclass 1 specific (1:100, Cat# 115‐545‐205, Cedarlane Laboratories), Cy™3 AffiniPure Fab Fragment Goat Anti‐Mouse IgM, μ chain specific (1:50, Cat# 115‐167‐020, Cedarlane Laboratories), and Alexa Fluor 594 (Cat# A11005, Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model

Collao

Sanders

Caminiti

et al. 2023

J cachexia sarcopenia muscle

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Background Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma that most often develops in children. Chemoradiation therapy is a standard treatment modality; however, the detrimental long-term skeletal muscle consequences of this therapy in juvenile cancer survivors include muscle atrophy and fibrosis resulting in decreased physical performance. Using a novel model of murine resistance and endurance exercise training, we investigate its role in preventing the long-term effects of juvenile RMS plus therapy. Methods Four-week-old male (n = 10) and female (n = 10) C57Bl/6J mice were injected with M3-9-M RMS cell into the left gastrocnemius with the right limb serving as an internal control (CON). Mice received a systemic vincristine injection and then five doses of 4.8 Gy of gamma radiation localized to the left hindlimb (RMS + Tx). Mice were then randomly divided into either sedentary (SED) or resistance and endurance exercise training (RET) groups. Changes in exercise performance, body composition, myocellular adaptations and the inflammatory/fibrotic transcriptome were assessed. Results RET improved endurance performance (P < 0.0001) and body composition (P = 0.0004) compared to SED. RMS + Tx resulted in significantly lower muscle weight (P = 0.015) and significantly smaller myofibre cross-sectional area (CSA) (P = 0.014). Conversely, RET resulted in significantly higher muscle weight (P = 0.030) and significantly larger Type IIA (P = 0.014) and IIB (P = 0.015) fibre CSA. RMS + Tx resulted in significantly more muscle fibrosis (P = 0.028), which was not prevented by RET. RMS + Tx resulted in significantly fewer mononuclear cells (P < 0.05) and muscle satellite (stem) cells (MuSCs) (P < 0.05) and significantly more immune cells (P < 0.05) than CON. RET resulted in significantly more fibro-adipogenic progenitors (P < 0.05), a trend for more MuSCs (P = 0.076) than SED and significantly more endothelial cells specifically in the RMS + Tx limb. Transcriptomic changes revealed significantly higher expression of inflammatory and fibrotic genes in RMS + Tx, which was prevented by RET. In the RMS + Tx model, RET also significantly altered expression of genes involved in extracellular matrix turnover. Conclusions Our study suggests that RET preserves muscle mass and performance in a model of juvenile RMS survivorship while partially restoring cellular dynamics and the inflammatory and fibrotic transcriptome.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model

Collao

Sanders

Caminiti

et al. 2023

J cachexia sarcopenia muscle

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“…From the mid‐belly of the gastrocnemius, 10‐μm‐thick sections were cut and mounted on a Premium Frosted Microscope Slides (Cat# 12‐544‐2, Fisher Scientific) using an HM 525 NX‐2210 cryostat. Masson's Trichrome staining was conducted by the Histology Core and the University of Ottawa as previously described 27 . A complete description of immunofluorescent protocols for Pax7, PDGFRα, CD31, F4/80, and CD206 are provided in the extended methods.…”

Section: Methodsmentioning

confidence: 99%

“…Masson's Trichrome staining was conducted by the Histology Core and the University of Ottawa as previously described. 27 A complete description of immunofluorescent protocols for Pax7, PDGFRα, CD31, F4/80, and CD206 are provided in the extended methods.…”

Section: Histochemical and Immunofluorescent Analysismentioning

confidence: 99%

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

Collao,

D'Souza,

Messeiller

et al. 2023

J cachexia sarcopenia muscle

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BackgroundRadiation‐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.MethodsFour‐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.ResultsJuvenile 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).ConclusionsOur 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.

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Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling

Flores-Opazo,

Kopinke,

Helmbacher

et al. 2024

Molecular Aspects of Medicine

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Weight loss with exercise improves muscle architecture and progenitor cell populations compared to weight loss alone in mice with preneoplastic colorectal lesions

Cited by 3 publications

References 55 publications

Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model

Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model

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

Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling

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