Dexamethasone exacerbates cisplatin‐induced muscle atrophy

Sakai, Hiroyasu; Kimura, Minami; Tsukimura, Yuka; Yabe, Saori; Isa, Yosuke; Kai, Yudai; Sato, Fumiaki; Kon, Risako; Ikarashi, Nobutomo; Narita, Minoru; Chiba, Yoshihiko; Kamei, Junzo

doi:10.1111/1440-1681.13024

Cited by 19 publications

(10 citation statements)

References 32 publications

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“…39 The mechanisms of muscle wasting by cisplatin are complex and multifactorial. In agreement with the findings of previous reports, 3 cisplatin caused direct atrophy of C2C12 myotubes, characterized by increases in the levels of ubiquitin ligase (MAFbx and MuRF-1) mRNA expressions 36 and decreases in the mRNA levels of myogenic regulatory factors (MyoD and myogenin). The effects of cisplatin treatment on C2C12 cells are considered predictive of impairment of the process of muscle differentiation.…”

Section: Discussionsupporting

confidence: 93%

D-Methionine Ameliorates Cisplatin-Induced Muscle Atrophy via Inhibition of Muscle Degradation Pathway

Liao

et al. 2019

Integr Cancer Ther

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Cisplatin induces anorexia, weight loss, loss of adipose tissue, skeletal muscle atrophy, and serious adverse effects that can cause premature termination of chemotherapy. The aim of this study was to use an animal model to assess cisplatin therapy (3 cycles) with and without d-methionine to investigate its protective effects on cisplatin-induced anorexia and skeletal muscle wasting. Wistar rats were divided into 3 groups and treated as follows: saline as control (group 1), intraperitoneal cisplatin once a week for 3 weeks (group 2), and intraperitoneal cisplatin once a week for 3 weeks plus oral administration of d-methionine (group 3). Tissue somatic index (TSI), gastric emptying index (GEI), and feeding efficiency were measured. Both hepatic lipid metabolism and muscle atrophy-related gene expressions and C2C12 myotubes were determined by polymerase chain reaction. Micro–computed tomography (micro-CT) was used to conduct assessment of bone microarchitecture indices. Pathological changes of the gastric mucosa were assessed by hematoxylin and eosin staining after euthanizing the animals. d-Methionine increased food intake, weight gain, gastric emptying, and feeding efficiency, as well as decrease stomach contents, after cisplatin injections. Cisplatin caused shortening of myofibers. Cisplatin-induced muscle mass wasting was mediated by the elevation of mRNA expressions of MAFbx and MuRF-1 in ubiquitin ligases in muscle tissue homogenate. The mRNA expressions of MyoD and myogenin, markers of muscle differentiation, declined following cisplatin administration. The administration of d-methionine not only led to significant improvements in myofiber diameter and cross-sectional fiber areas but also reversed muscle atrophy-related gene expression. However, there were no significant changes in stomach histology or microarchitecture of trabecular bone among the study groups. The results indicate that d-methionine has an appetite-enhancing effect and ameliorates cisplatin-induced adipose and muscle tissue loss during cisplatin-based chemotherapy.

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Section: Discussionsupporting

confidence: 93%

D-Methionine Ameliorates Cisplatin-Induced Muscle Atrophy via Inhibition of Muscle Degradation Pathway

Liao

et al. 2019

Integr Cancer Ther

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“…For example, the therapeutic utility of multi-kinase inhibitors is becoming increasingly prevalent [ 225 ] and they demonstrably have cachexia-inducing properties [ 226 , 227 ]. Additionally, drug compounds that are utilised to mitigate the side-effects of clinical chemotherapy treatment such as the well-described gastrointestinal toxicities elicited by dexamethasone [ 228 ] need to be stratified for their capacity to potentiate chemotherapy-induced cachectic myopathy [ 229 , 230 ].…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

Campelj

Goodman

Rybalka

2021

Cancers

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Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer–host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer–host interaction side of cancer cachexia, often overlooking the capability of chemotherapy to induce cachectic myopathy. Accumulating evidence in experimental models of cachexia suggests that some chemotherapeutic agents rapidly induce cachectic myopathy, although the underlying mechanisms responsible vary between agents. Importantly, we highlight the capacity of specific chemotherapeutic agents to induce cachectic myopathy, as not all chemotherapies have been evaluated for cachexia-inducing properties—alone or in clinically compatible regimens. Furthermore, we discuss the experimental evidence surrounding therapeutic strategies that have been evaluated in chemotherapy-induced cachexia models, with particular focus on exercise interventions and adjuvant therapeutic candidates targeted at the mitochondria.

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“…The preparation of protein sample homogenate solutions and western blot analyses were performed as previously described. 18 The following primary rabbit antibodies were used: anti-IGF-1 (1:1000 dilution; PeproTech), anti-IGF-1R beta chain (1:1000 dilution; Proteintech Group, Inc., IL, USA), anti-MuRF1 (1:1000 dilution; ECM Biosciences, Versailles, KY, USA), anti-atrogin-1 (1:1000 dilution; ECM Biosciences), anti-Foxo3a (1:1000 dilution; Cell Signaling Technology, Danvers, MA, USA), anti-Akt (1:1000; Cell Signaling Technology), anti-phospho-Akt (1:1000; Cell Signaling Technology), anti-phospho-Foxo3a (1:1000; Cell Signaling Technology), anti-Smad2 (1:1000; Cell Signaling Technology) antiphospho-Smad2/Smad3 (1:1000; Cell Signaling Technology), and anti-phospho-Smad2 (1:1000; Cell Signaling Technology). The horseradish peroxidase-linked secondary antibodies used were goat anti-rabbit IgG (Cell Signaling Technology).…”

Section: Western Blotsmentioning

confidence: 99%

“…The mRNA levels of various genes were examined using qRT-PCR as previously described. 18 Briefly, total RNA was extracted from femoral quadriceps muscles using a one-step guanidinium-phenol-chloroform extraction procedure with the TRI Reagent ™ cDNAs prepared from total RNA (1.0 μg) using the ReverTra Ace qPCR RT Master Mix with gDNA Remover (Toyobo, Osaka, Japan). The diluted reaction mixture (2 μL) was subjected to PCR (50-nM forward and reverse primers, Fast SYBR Green Master Mix; Thermo Fisher Scientific, Waltham, MA, USA) in a final volume of 10 μL.…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

Exogenous insulin‐like growth factor 1 attenuates cisplatin‐induced muscle atrophy in mice

Sakai

Asami

Naito

et al. 2021

J cachexia sarcopenia muscle

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Background A reduction in the skeletal muscle mass worsens the prognosis of patients with various cancers. Our previous studies indicated that cisplatin administration to mice caused muscle atrophy. This is a concern for human patients receiving cisplatin. The insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway stimulates the rate of protein synthesis in skeletal muscle. Thus, IGF-I can be a central therapeutic target for preventing the loss of skeletal muscle mass in muscle atrophy, although it remains unclear whether pharmacological activation of the IGF-1/PI3K/Akt pathway attenuates muscle atrophy induced by cisplatin. In this study, we examined whether exogenous recombinant human IGF-1 attenuated cisplatin-induced muscle atrophy. Methods Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for four consecutive days. On Day 5, quadriceps muscles were isolated. Mecasermin (recombinant human IGF-1) or the vehicle control was subcutaneously administered 30 min prior to cisplatin administration. A dietary restriction group achieving weight loss equivalent to that caused by cisplatin administration was used as a second control. C2C12 myotubes were treated with cisplatin with/without recombinant mouse IGF-1. The skeletal muscle protein synthesis/degradation pathway was analysed by histological and biochemical methods. Results Cisplatin reduced protein level of IGF-1 by about 85% compared with the vehicle group and also reduced IGF-1/PI3K/Akt signalling in skeletal muscle. Under this condition, the protein levels of muscle ring finger protein 1 (MuRF1) and atrophy gene 1 (atrogin-1) were increased in quadriceps muscles (MuRF1; 3.0 ± 0.1 folds, atrogin-1; 3.0 ± 0.3 folds, P < 0.001, respectively). The administration of a combination of cisplatin and IGF-1 significantly suppressed the cisplatin-induced downregulation of IGF-1/PI3K/Akt signalling and upregulation of MuRF1 and atrogin-1 (up to 1.6 ± 0.3 and 1.5 ± 0.4 folds, P < 0.001, respectively), resulting in diminished muscular atrophy. IGF-1 showed similar effects in cisplatin-treated C2C12 myotubes, as well as the quadriceps muscle in mice. Conclusions The downregulation of IGF-1 expression in skeletal muscle might be one of the factors playing an important role in the development of cisplatin-induced muscular atrophy. Compensating for this downregulation with exogenous IGF-1 suggests that it could be a therapeutic target for limiting the loss of skeletal muscle mass in cisplatin-induced muscle atrophy.

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Dexamethasone exacerbates cisplatin‐induced muscle atrophy

Cited by 19 publications

References 32 publications

D-Methionine Ameliorates Cisplatin-Induced Muscle Atrophy via Inhibition of Muscle Degradation Pathway

D-Methionine Ameliorates Cisplatin-Induced Muscle Atrophy via Inhibition of Muscle Degradation Pathway

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

Exogenous insulin‐like growth factor 1 attenuates cisplatin‐induced muscle atrophy in mice

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