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.

Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction

“…or saline treatment (equal volume). This dose of DOX has been scaled for use in rats and is a regularly used animal dose that is within the range used for humans [26,27]. This dose is well-established to induce skeletal muscle dysfunction in animals [8,28,29].…”

Sodium nitrate co-supplementation does not exacerbate low dose metronomic doxorubicin-induced cachexia in healthy mice

“…Mice were administered with either VEH (0.9% NaCl) or DOX (4 mg/kg in 0.9% NaCl; Sigma Aldrich, Australia) via intraperitoneal injection 3 times over a 7 day period (i.e. on day 1, 3 and 5; for a cumulative dose of 12 mg/kg) which is the equivalent to a low cumulative clinical dose 5,75 , thus depicting a model of LDM DOX administration. SN was co-supplemented in drinking water ( 85 mg/L −1 (1 mM) (Sigma Aldrich, Australia)) throughout the duration of the LDM DOX regimen in a third group of animals (DOX + SN group).…”

“…4E) but had no effect on oxidative fibres, suggestive of nitrate-mediated fibre type transformation from IIb to IIa type. plex I of the mitochondrial ETC, DOX is a well-known inducer of superoxide production as a by-product of its metabolism 4,5,13 . Similarly, we have previously demonstrated that in a pro-oxidant environment, SN co-supplementation has a damaging effect on skeletal muscle secondary to a higher peroxynitrite production 37 .…”

Physical exercise—A toxin‐free complement to cancer therapy

“…For example utilization of ATP 21 and glycogen 22 adapts and myocellular gene expression and protein synthesis depends on muscle excitation and tension 23 . A meta‐analysis on the molecular pathways responsible for chemotherapy‐induced skeletal muscle atrophy 24 concludes that in preclinical models, muscle mass and even more muscle strength decreased in response to doxorubicin administration. In addition to proteolytic changes and a decreased protein synthesis, mitochondrial dysfunction seems to be one key player.…”