Dataset Information

Doxorubicin-induced skeletal muscle atrophy: Elucidating the underlying molecular pathways.

ABSTRACT:

Aim

Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models.

Methods

A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool.

Results

Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross-sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin-induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin-proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin-induced muscle atrophy, the activation of the ubiquitin-proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway.

Conclusion

The results of the meta-analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose-response, separate the effects of doxorubicin from tumour-induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches.

SUBMITTER: Hiensch AE

PROVIDER: S-EPMC7317437 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Doxorubicin-induced skeletal muscle atrophy: Elucidating the underlying molecular pathways.

Hiensch Anouk E AE Bolam Kate A KA Mijwel Sara S Jeneson Jeroen A L JAL Huitema Alwin D R ADR Kranenburg Onno O van der Wall Elsken E Rundqvist Helene H Wengstrom Yvönne Y May Anne M AM

Acta physiologica (Oxford, England) 20191031 2

<h4>Aim</h4>Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models.<h4>Methods</h4>A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included s ...[more]

PMID: 31600860

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Project description:Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention.We addressed this question both in vitro using differentiated myotubes treated with TNF-?, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-? was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-?, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy.Ceramide accumulation induced by TNF-? or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations.

Dataset Information

Doxorubicin-induced skeletal muscle atrophy: Elucidating the underlying molecular pathways.

Aim

Methods

Results

Conclusion

Publications

Doxorubicin-induced skeletal muscle atrophy: Elucidating the underlying molecular pathways.

Similar Datasets

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