A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo, Míriam; Penna, Fabio; Oliva, Francesc; Luque, Melani; Betancourt, Angélica; Marmonti, Enrica; López‐Soriano, Francisco J.; Argilés, Josep Μ.; Busquets, Sı́lvia

doi:10.1002/jcsm.12035

Cited by 45 publications

(44 citation statements)

References 45 publications

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“…34 Myostatin (also known as GDF-8) is a negative regulator of muscle mass, which binds primarily to the activin II B receptor. 122 Megestrol acetate alone reduced autophagy in the heart and improved cardiac function in experimental cancer. 111 Human myocardium expressed myostatin in end-stage heart failure and the related signalling pathways in the myocardium seen to have a gender effect.…”

Section: Chronic Heart Failure and Muscle Maintenancementioning

confidence: 99%

Skeletal muscle wasting in chronic heart failure

2018

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Patients suffering from chronic heart failure (CHF) show an increased prevalence (~20% in elderly CHF patients) of loss of muscle mass and muscle function (i.e. sarcopenia) compared with healthy elderly people. Sarcopenia, which can also occur in obese patients, is considered a strong predictor of frailty, disability, and mortality in older persons and is present in 5–13% of elderly persons aged 60–70 years and up to 50% of all octogenarians. In a CHF study, sarcopenia was associated with lower strength, reduced peak oxygen consumption (peak VO2, 1173 ± 433 vs. 1622 ± 456 mL/min), and lower exercise time (7.7 ± 3.8 vs. 10.22 ± 3.0 min, both P < 0.001). Unfortunately, there are only very limited therapy options. Currently, the main intervention remains resistance exercise. Specialized nutritional support may aid the effects of resistance training. Testosterone has significant positive effects on muscle mass and function, and low endogenous testosterone has been described as an independent risk factor in CHF in a study with 618 men (hazard ratio 0.929, P = 0.042). However, the use of testosterone is controversial because of possible side effects. Selective androgen receptor modulators have been developed to overcome these side effects but are not yet available on the market. Further investigational drugs include growth hormone, insulin‐like growth factor 1, and several compounds that target the myostatin pathway. The continuing development of new treatment strategies and compounds for sarcopenia, muscle wasting regardless of CHF, and cardiac cachexia makes this a stimulating research area.

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Section: Chronic Heart Failure and Muscle Maintenancementioning

confidence: 99%

Skeletal muscle wasting in chronic heart failure

2018

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“…Cisplatin was also show to up-regulate the expression of myostatin, a member of the TGF-beta family of growth factors also known to negatively regulate muscle mass in the occurrence of cancer, thus contributing to muscle wasting via activation of proteasome-dependent muscle catabolism [11–13]. Similarly, sorafenib, a multi-kinase inhibitor successfully tested for the treatment of several kinds of pre-clinical tumor models [14], was shown to promote muscle wasting in association with the activation of the ubiquitin-and Ca 2+ -dependent proteolytic systems [15]. …”

Section: Introductionmentioning

confidence: 99%

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

et al. 2016

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Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.

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“…The stimulation of β 2 ‐adrenoceptors (AR) has attracted the attention of clinicians for preventing or even reversing the muscle wasting and weakness in several pathological conditions, including cancer cachexia, sarcopenia, and muscular dystrophies . In addition to changes in trophism, strength gain by β 2 ‐agonists may be also achieved by switching from slow‐oxidative to fast‐glycolytic fibre type, which present the highest force development .…”

Section: Introductionmentioning

confidence: 99%

Insulin/IGF1 signalling mediates the effects of β₂‐adrenergic agonist on muscle proteostasis and growth

Gonçalves

Silveira

Manfredi

et al. 2019

J cachexia sarcopenia muscle

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Background Stimulation of β 2 ‐adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive. Methods Fed wild type (WT), 2‐day fasted WT, muscle‐specific insulin (INS) receptor (IR) knockout (M‐IR −/− ), and MKR mice were studied with regard to acute effects of the β 2 ‐agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 μg kg −1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 μg kg −1 day −1 ) for 30 days. Results In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3‐II content, 65%, P ≤ 0.05) that was paralleled by an increase in serum INS levels (4‐fold to 25‐fold, P ≤ 0.05) and the phosphorylation of Akt (4.4‐fold to 6.5‐fold, P ≤ 0.05) and ERK1/2 (50% to two‐fold, P ≤ 0.05). This led to the suppression (40–70%, P ≤ 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ≤ 0.05) protein synthesis only in fed condition and stimulated (4.4‐fold to 35‐fold, P ≤ 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M‐IR −/− and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of β 2 ‐adrenoceptors in fed WT mice increased body (11%, P ≤ 0.05) and muscle (15%, P ≤ 0.05) growth and downregulated atrophy‐related genes (30–40%, P ≤ 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ≤ 0.05) were only partially impaired in MKR mice (12%, P ≤ 0.05), and FOR‐induced slow‐to‐fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ≤ 0.05) in the number of centrally nucleat...

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A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Cited by 45 publications

References 45 publications

Skeletal muscle wasting in chronic heart failure

Skeletal muscle wasting in chronic heart failure

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

Insulin/IGF1 signalling mediates the effects of β₂‐adrenergic agonist on muscle proteostasis and growth

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A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Cited by 45 publications

References 45 publications

Skeletal muscle wasting in chronic heart failure

Skeletal muscle wasting in chronic heart failure

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth

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Insulin/IGF1 signalling mediates the effects of β₂‐adrenergic agonist on muscle proteostasis and growth