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

Collao, Nicolás; Sanders, Olivia J.; Caminiti, Taylor; Messeiller, Laura; Lisio, Michael De

doi:10.1002/jcsm.13185

Cited by 10 publications

(10 citation statements)

References 39 publications

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“…Regardless, the structural (e.g., TAs) and functional (e.g., specific force deficit) impact of the G100S TAM mutation in Orai1 on skeletal muscle may best be addressed in part through a combination of endurance exercise in conjunction with resistance or high-intensity interval training exercise that is better suited to increase muscle hypertrophy and strength, particularly in type II fibers (89)(90)(91)(92)(93).…”

Section: Discussionmentioning

confidence: 99%

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

O’Connor,

Zhao,

Orciuoli

et al. 2023

Preprint

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Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+entry (SOCE): STIM1 Ca2+sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.

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Section: Discussionmentioning

confidence: 99%

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

O’Connor,

Zhao,

Orciuoli

et al. 2023

Preprint

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“…Nutrition and physical activity had been suggested to maintain muscle; however, the effectiveness of nutrition and physical activity can be limited in patients with increased systemic inflammation. [28][29][30] Potential anti-inflammatory interventions include eicosapentaenoic acid and some targeted anti-inflammatory medications including anti-interleukin-6 (IL-6) therapy or combined betablocker and cyclooxygenase 2 inhibition. [31][32][33][34][35] Exercise may also help reduce systemic inflammation and improve muscle in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that anti‐inflammatory interventions may modulate systemic inflammation to help preserve muscle during treatment for these patients. Nutrition and physical activity had been suggested to maintain muscle; however, the effectiveness of nutrition and physical activity can be limited in patients with increased systemic inflammation 28–30 . Potential anti‐inflammatory interventions include eicosapentaenoic acid and some targeted anti‐inflammatory medications including anti‐interleukin‐6 (IL‐6) therapy or combined beta‐blocker and cyclooxygenase 2 inhibition 31–35 .…”

Section: Discussionmentioning

confidence: 99%

Explainable machine learning model for predicting skeletal muscle loss during surgery and adjuvant chemotherapy in ovarian cancer

Hsu

Weng

et al. 2023

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on computed tomography (CT) scans, this labour‐intensive process can impair its utility in clinical practice. This study aimed to develop a machine learning (ML) model to predict muscle loss based on clinical data and to interpret the ML model by applying SHapley Additive exPlanations (SHAP) method.MethodsThis study included the data of 617 patients with ovarian cancer who underwent primary debulking surgery and platinum‐based chemotherapy at a tertiary centre between 2010 and 2019. The cohort data were split into training and test sets based on the treatment time. External validation was performed using 140 patients from a different tertiary centre. The skeletal muscle index (SMI) was measured from pre‐ and post‐treatment CT scans, and a decrease in SMI ≥ 5% was defined as muscle loss. We evaluated five ML models to predict muscle loss, and their performance was determined using the area under the receiver operating characteristic curve (AUC) and F1 score. The features for analysis included demographic and disease‐specific characteristics and relative changes in body mass index (BMI), albumin, neutrophil‐to‐lymphocyte ratio (NLR), and platelet‐to‐lymphocyte ratio (PLR). The SHAP method was applied to determine the importance of the features and interpret the ML models.ResultsThe median (inter‐quartile range) age of the cohort was 52 (46–59) years. After treatment, 204 patients (33.1%) experienced muscle loss in the training and test datasets, while 44 (31.4%) patients experienced muscle loss in the external validation dataset. Among the five evaluated ML models, the random forest model achieved the highest AUC (0.856, 95% confidence interval: 0.854–0.859) and F1 score (0.726, 95% confidence interval: 0.722–0.730). In the external validation, the random forest model outperformed all ML models with an AUC of 0.874 and an F1 score of 0.741. The results of the SHAP method showed that the albumin change, BMI change, malignant ascites, NLR change, and PLR change were the most important factors in muscle loss. At the patient level, SHAP force plots demonstrated insightful interpretation of our random forest model to predict muscle loss.ConclusionsExplainable ML model was developed using clinical data to identify patients experiencing muscle loss after treatment and provide information of feature contribution. Using the SHAP method, clinicians may better understand the contributors to muscle loss and target interventions to counteract muscle loss.

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“…FAPs provide pro‐myogenic signals essential for muscle growth, maintenance, and regeneration 11,12 . First described as regulators of myogenic differentiation during regeneration, 10 recent work has identified a role for FAPs in myoblast activation, 13 muscle growth, 14 ,S10,S11 and maintenance 15 . FAPs regulate these processes primarily via paracrine mechanisms 16 ,S12 with pro‐myogenic subpopulations beginning to be identified 17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, in diverse muscle pathologies, with excess ECM deposition, FAPs expand, and localize to fibrotic areas 22–24 . S13,S14 In a murine model of pediatric cancer plus radiation therapy, an increase in inflammatory and pro‐fibrotic genes was observed, 14 accompanied by lifelong muscle fibrosis 25 . At the cellular level, activated myofibroblasts which are derived from FAPs and express stress fibres with highly contractile properties, are mainly responsible for ECM synthesis and deposition S15 .…”

Section: Introductionmentioning

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

Cited by 10 publications

References 39 publications

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

Explainable machine learning model for predicting skeletal muscle loss during surgery and adjuvant chemotherapy in ovarian cancer

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

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