Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy

Malavaki, Christina J.; Sakkas, Giorgos K.; Mitrou, Georgia I.; Kalyva, Athanasia; Stefanidis, Ioannis; Myburgh, Kathryn H.; Karatzaferi, Christina

doi:10.1007/s10974-015-9439-8

Cited by 48 publications

(45 citation statements)

References 142 publications

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“…When comparing the results of this meta‐analysis to other models of skeletal muscle atrophy, we found that a 7‐day hind limb suspension resulted in a comparable decrease in soleus (27.1%) and gastrocnemius muscle (21.5%) weight to body weight ratio in wildtype mice . Moreover, evidence shows that the network of interacting signalling pathways that we found to be involved in doxorubicin‐induced skeletal muscle atrophy, also share common pathways with disuse atrophy . Given the similarities between these two models of skeletal muscle atrophy, we hypothesize that disuse might be involved in doxorubicin‐induced skeletal muscle atrophy.…”

Section: Discussionmentioning

confidence: 64%

Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 64%

Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways

et al. 2019

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“…While it has been suggested that rodents are a poor model for the study of human disuse atrophy due to inherent biological differences (39), recent data suggest that the response to disuse is actually quite similar between humans and rodents (38). There are many potential explanations for the discrepancies between the human and rodent studies; two of the most likely are 1) the duration and experimental model used to study disuse-induced muscle atrophy, and 2) the muscles and time points selected for analysis (31,37). To determine the extent to which changes in protein synthesis and/or protein degradation contribute to muscle atrophy under conditions of disuse, we chose to use the hindlimb suspension model.…”

mentioning

confidence: 99%

Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

Baehr

West

Marshall

et al. 2017

Journal of Applied Physiology

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Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (-9 to -38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy.

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“…Skeletal muscle is susceptible to several types of injury including direct trauma, crush, eccentric exercise, neurologic dysfunction, and innate genetic defects. In addition to atrophy, severe and repetitive muscle damage may reduce the quality of life and increase the risks of mortality and morbidity (14, 15). Muscle damage has been reported in patients with COPD (16) and during peripheral ischemia (17), 2 diseases associated with cellular hypoxia and muscle atrophy (16, 18).…”

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confidence: 99%

Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity

Chaillou

Lanner

2016

FASEB j.

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Reduced oxygen (O) levels (hypoxia) are present during embryogenesis and exposure to altitude and in pathologic conditions. During embryogenesis, myogenic progenitor cells reside in a hypoxic microenvironment, which may regulate their activity. Satellite cells are myogenic progenitor cells localized in a local environment, suggesting that the O level could affect their activity during muscle regeneration. In this review, we present the idea that O levels regulate myogenesis and muscle regeneration, we elucidate the molecular mechanisms underlying myogenesis and muscle regeneration in hypoxia and depict therapeutic strategies using changes in O levels to promote muscle regeneration. Severe hypoxia (≤1% O) appears detrimental for myogenic differentiation in vitro, whereas a 3-6% O level could promote myogenesis. Hypoxia impairs the regenerative capacity of injured muscles. Although it remains to be explored, hypoxia may contribute to the muscle damage observed in patients with pathologies associated with hypoxia (chronic obstructive pulmonary disease, and peripheral arterial disease). Hypoxia affects satellite cell activity and myogenesis through mechanisms dependent and independent of hypoxia-inducible factor-1α. Finally, hyperbaric oxygen therapy and transplantation of hypoxia-conditioned myoblasts are beneficial procedures to enhance muscle regeneration in animals. These therapies may be clinically relevant to treatment of patients with severe muscle damage.-Chaillou, T. Lanner, J. T. Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity.

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Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy

Cited by 48 publications

References 142 publications

Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways

Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways

Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity

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