Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

Ballarò, Riccardo; Beltrà, Marc; Lucia, Serena De; Pin, Fabrizio; Ranjbar, Kia; Hulmi, Juha J.; Costelli, Paola; Penna, Fabio

doi:10.1096/fj.201801862r

Cited by 77 publications

(122 citation statements)

References 51 publications

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“…In this regard, healthy mice treated with FOLFOX or FOLFIRI (the combination of 5-fluorouracil and leucovorin with either oxaliplatin or irinotecan, respectively) present with reduced mitochondrial mass and oxidative capacity in the skeletal muscle [20] . Similar results have been reported in C26-bearing mice treated with chemotherapy (oxaliplatin and 5-fluorouracil) [21] , showing that anti-cancer treatment significantly increased the lifespan of C26-bearing mice but exacerbate muscle wasting as compared to untreated C26 hosts [21] . Such wasting effect has been associated with reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and cytochrome c expression and with increased markers of mitophagy, together with impaired oxidative capacity and ATP levels [21] .…”

Section: Introductionsupporting

confidence: 83%

“…Similar results have been reported in C26-bearing mice treated with chemotherapy (oxaliplatin and 5-fluorouracil) [21] , showing that anti-cancer treatment significantly increased the lifespan of C26-bearing mice but exacerbate muscle wasting as compared to untreated C26 hosts [21] . Such wasting effect has been associated with reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and cytochrome c expression and with increased markers of mitophagy, together with impaired oxidative capacity and ATP levels [21] . Using a proteomic approach, alterations of the tricarboxylic acid (TCA) cycle and impaired expression of markers of mitochondrial fusion, fission and biogenesis have been reported in both untreated and chemotherapy-treated C26-bearing mice [22] .…”

Section: Introductionsupporting

confidence: 83%

“…On the contrary, endurance exercise with treadmill in a flat mode does not succeed in improving cachexia in C26 hosts [35] . The effect of exercise trough a motorized wheel has also been tested in a model of cancer (C26 tumor) and chemotherapy-induced muscle wasting, partially preventing the loss of muscle mass and strength [21] . These improvements are associated with a partial restoration of mitochondrial homeostasis [21] .…”

Section: Exercise As a Modulator Of Muscle Metabolismmentioning

confidence: 99%

“…The effect of exercise trough a motorized wheel has also been tested in a model of cancer (C26 tumor) and chemotherapy-induced muscle wasting, partially preventing the loss of muscle mass and strength [21] . These improvements are associated with a partial restoration of mitochondrial homeostasis [21] . Notably, exercise increases mitochondrial mass, normalizes the levels of PINK1, BNIP3 and Mfn2, improves the succinate dehydrogenase (SDH) activity and increases energy stores [21] .…”

Section: Exercise As a Modulator Of Muscle Metabolismmentioning

confidence: 99%

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Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

Ballarò¹,

Penna²,

Ferraro³

et al. 2019

JCMT

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Cancer cachexia is a debilitating syndrome mainly characterized by muscle and fat wasting, leading to the progressive loss of body weight and complicating the management of cancer patient. In particular, the loss of muscle weight is a negative prognostic factor, being associated with chemotherapy toxicity and reduced survival. Increased inflammation and protein dysmetabolism are some of the impairments that lead to muscle wasting in cancer patients. Together with these alterations, tumor growth and chemotherapy administration may affect mitochondrial function, impinging on the muscle energy metabolism. Indeed, therapeutic approaches poised to correct both hypercatabolism and mitochondrial alterations could be effective in preventing cancer-induced muscle wasting. Among the non-pharmacological approaches, exercise training is one of the best modulator of muscle physiology able to impinge on both protein and energy metabolism. However, the wasting phenotype that characterizes cancer patients could be not compatible with physical training, prompting the development of different strategies to improve muscle metabolism. The aim of this mini-review is to discuss both the beneficial effects and the limitations of exercise training in cancer cachexia and the adoption of drugs able to modulate exercise-induced pathways.

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Section: Introductionsupporting

confidence: 83%

Section: Introductionsupporting

confidence: 83%

Section: Exercise As a Modulator Of Muscle Metabolismmentioning

confidence: 99%

Section: Exercise As a Modulator Of Muscle Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

Ballarò¹,

Penna²,

Ferraro³

et al. 2019

JCMT

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“…The administration of IL4 to the C26 hosts resulted in increased tumour mass (Supporting Information, ) that however does not necessarily reflect an increased number of tumour cells. Indeed, the H&E staining revealed that more than 30% of tumour area in the IL4‐treated C26‐bearing mice (sacrificed at Day 31 after C26 cell injection) was necrotic (eosin positive) probably surrounded by small inflammatory cell infiltrate, a pattern that could not be observed in tumours isolated from C26 hosts (Day 13 after C26 implantation; Figure A and B) . A possible limitation of these results is that the histological analysis compares Day 13 C26 with Day 31 C26 + IL4 tumours.…”

Section: Resultsmentioning

confidence: 91%

Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice

Costamagna¹,

Duelen²,

Penna

et al. 2020

J cachexia sarcopenia muscle

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Background Anorexia, body wasting, inflammation, muscle, and adipose tissue loss are hallmarks of cancer cachexia, a syndrome that affects the majority of cancer patients, impairing their ability to endure chemotherapeutic therapies and reducing their lifespan. In the last 10 years, alterations of protein turnover and impairment of adult myogenesis have been proposed as major contributing factors. Methods Muscle stem cells, including satellite cells, mesoangioblasts, and fibroadipogenic progenitors, were isolated and characterized from C26 colon carcinoma‐bearing (C26) mice. Circulating levels of interleukin‐4/13 (IL4/IL13) were analysed by ELISA, and the effects of IL4 on muscle mass and function, protein synthesis, muscle regeneration, and myogenic progenitor cell number were analysed at both functional (treadmill and grip test) and molecular levels (qRT–PCR, immunofluorescence analysis, surface sensing of translation, and western blot). The Kaplan–Meier test was used to analyse the survival curve of IL4‐treated and IL4‐untreated C26 mice. Results The administration of IL4 to C26 mice rescued muscle mass by increasing protein synthesis. The IL4 treatment improved performances and prolonged survival of C26 mice. IL4 administration re‐established both number and function of satellite cells and fibroadipogenic progenitors without affecting mesoangioblasts in C26 mice, rescuing myogenesis. Upon IL4 treatment, a high number of cytotoxic lymphocytes and type II macrophages were observed with a subsequent increase in necrotic areas of C26 tumours. Conclusions The results here presented shed new light on IL4 signalling during muscle wasting and early stages of muscle regeneration that explain the beneficial effect observed in IL4‐treated C26 mice. These findings might aid to develop therapeutic approaches to improve mobility and quality of life in cachectic patients.

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Extracellular vesicles derived from tumour cells as a trigger of energy crisis in the skeletal muscle

Beltrà

Garcia‐Castillo

et al. 2021

J cachexia sarcopenia muscle

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Background Cachexia, a syndrome frequently occurring in cancer patients, is characterized by muscle wasting, altered energy and protein metabolism and impaired myogenesis. Tumour‐derived microvesicles (TMVs) containing proteins, messenger RNAs (mRNAs), and non‐coding RNAs could contribute to cancer‐induced muscle wasting. Methods Differential ultracentrifugation was used to isolate TMVs from the conditioned medium of Lewis lung carcinoma and C26 colon carcinoma cell cultures. TMVs were added to the culture medium of C2C12 myoblasts and myotubes for 24–48–72 h, and the effects on protein and energy metabolism were assessed. TMVs were also isolated from the blood of C26‐bearing mice. MicroRNA (miR) profile of TMVs was obtained by RNA‐seq and validated by digital drop PCR. Selected miRs were overexpressed in C2C12 myoblasts to assess the effects on myogenic differentiation. Results Differentiation was delayed in C2C12 myoblasts exposed to TMVs, according to reduced expression of myosin heavy chain (MyHC; about 62% of controls at Day 4) and myogenin (about 68% of controls at Day 4). As for myotubes, TMVs did not affect the expression of MyHC, while revealed able to modulate mitochondria and oxidative metabolism. Indeed, reduced mRNA levels of PGC‐1α (C = 1 ± 0.2, TMV = 0.57 ± 0.06, normalized fold change, P < 0.05) and Cytochrome C (C = 1 ± 0.2, TMV = 0.65 ± 0.04, normalized fold change, P < 0.05), associated with increased BNIP3 expression (C = 1 ± 0.1, TMV = 1.29 ± 0.2, normalized fold change, P < 0.05), were observed, suggesting reduced mitochondrial biogenesis/amount and enhanced mitophagy. These changes were paralleled by decreased oxygen consumption (C = 686.9 ± 44 pmol/min, TMV = 552.25 ± 24 pmol/min, P < 0.01) and increased lactate levels (C = 0.0063 ± 0.00045 nmol/μL, TMV = 0.0094 ± 0.00087 nmol/μL, P < 0.01). A total of 118 miRs were found in MVs derived from the plasma of the C26 hosts; however, only three of them were down‐regulated (RNA‐seq): miR‐181a‐5p (−1.46 fold change), miR‐375‐3p (−2.52 fold change), and miR‐455‐5p (−3.87 fold change). No correlation could be observed among miRs in the MVs obtained from the blood of the C26 host and those released by C26 cells in the culture medium. Overexpression of miR‐148a‐3p and miR‐181a‐5p in C2C12 myoblasts revealed the ability to impinge on the mRNA levels of Myf5, Myog, and MyHC (Myh4 and Myh7). Conclusions These results show that in C2C12 cultures, TMVs are able to affect both differentiation and the mitochondrial system. Such effects could be related to TMV‐contained miRs.

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Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

Cited by 77 publications

References 51 publications

Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice

Extracellular vesicles derived from tumour cells as a trigger of energy crisis in the skeletal muscle

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