Doxorubicin interacts directly with skinned single skeletal muscle fibres

Beer, E. L. de; Finkle, Heather; Voest, Emile E.; Heijst, Bas G. V. Van; Schiereck, P.

doi:10.1016/0014-2999(92)90103-b

Cited by 22 publications

(8 citation statements)

References 8 publications

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“…Previous studies have shown that DOX is able to generate muscle dysfunction, leading to lost performance and the physical appearance of debilitating fatigue . Worsening in the parameters of maximum strength, maximum relaxation and fatigue were evident and were probably caused by changes in sarcoplasmic calcium metabolism …”

Section: Introductionmentioning

confidence: 95%

“…[17][18][19] Worsening in the parameters of maximum strength, maximum relaxation and fatigue were evident and were probably caused by changes in sarcoplasmic calcium metabolism. 20,21 However, few studies have been proposed to investigate a possible association between the use of DOX and insulin resistance, as well as the role of skeletal muscle in the process.…”

Section: Introductionmentioning

confidence: 99%

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Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle

Lima

Yamashita

Pimentel

et al. 2016

J cachexia sarcopenia muscle

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BackgroundCancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP‐activated protein kinase) in GLUT‐4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process.MethodsWe used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15 mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5‐aminoimidazole‐4‐carboxamide (AICAR)] and the antioxidant n‐acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability.ResultsThe animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT‐4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR.ConclusionsDOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle

Lima

Yamashita

Pimentel

et al. 2016

J cachexia sarcopenia muscle

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“…The pCa for half-maximal activation (pCa 50 =-log 10 K) indicates the apparent Ca 2+ sensitivity of contractile proteins, and the Hill coefficient (n H ) allows us to estimate the degree of co-operativity [4]. These two parameters were calculated for each experiment using linear regression analysis.…”

Section: Experimental Protocolmentioning

confidence: 99%

Rapid cooling-induced contractures in rat skinned skeletal muscle fibres originate from sarcoplasmic reticulum Ca2+ release through ryanodine and inositol trisphosphate receptors

Talon¹,

Huchet-Cadiou²,

Léoty³

2000

Pflügers Arch - Eur J Physiol

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Previous reports have shown that cooling striated muscles induces contractile responses that are related to Ca2+ release from the sarcoplasmic reticulum. However, the effect of cooling has generally been studied in the presence of pharmacological agents that potentiate rapid cooling-induced contractures. The present study shows that in saponin-skinned rat skeletal muscle preparations, a drop in temperature from 22 degrees C to 2 degrees C per se induces a contracture which relaxes on return to 22 degrees C. In fast-twitch fibres, rapid cooling-induced contractures are fully blocked by ryanodine, an inhibitor of ryanodine receptors. By contrast, in slow-twitch fibres, ryanodine partially inhibits the rapid cooling-induced contractile response, leaving a residual tension that dissipates after application of inositol 1,4,5-trisphosphate (InsP3). At low concentrations, heparin, an inhibitor of InsP3 receptors, decreases rapid cooling-induced contractures in both types of muscle. The present results suggest that in skeletal muscle, rapid cooling-induced contractures are due to both ryanodine-sensitive and InsP3-sensitive Ca2+ release from the sarcoplasmic reticulum.

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“…It has now been commonly recognized, however, that DOX myotoxicity is a clinically relevant side effect. In vitro DOX treatment increases calcium release from isolated skeletal muscle sarcoplasmic reticulum 20 , and at the whole muscle level, in vitro DOX incubation interferes with actin-myosin interaction and decreases calcium sensitivity 21 . Furthermore, myotubes incubated with DOX have impaired maximal force production and maximal relaxation velocity as well as increased fatigue rates 22 .…”

Section: Discussionmentioning

confidence: 99%

Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression

Hydock¹

2017

MLTJ

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SummaryBackground: The skeletal muscle toxicity that accompanies the chemotherapy drug doxorubicin (DOX) may lead to cancer patient weakness and fatigue. This myotoxicity involves myogenic regulatory factor (MRF) disruption which alters muscle integrity and regeneration. Endurance exercise enhances MRF expression and thereby may mitigate DOX-induced MRF disruptions. This study examined the effects of endurance training and DOX treatment on myogenic regulatory factor (MRF) expression. Methods: Male rats were exercise trained (EXER) or remained sedentary (SED) for two weeks. EXER and SED then received either DOX (15 mg/kg) or saline (SAL). Soleus, extensor digitorum longus (EDL), and diaphragm were excised 24 hours post injection, and MRF expression was analyzed. Results: Significant Myf5 drug and activity effects were observed in the soleus with EXER+DOX expressing higher Myf5 than SED+DOX. A significant drug effect was detected in soleus MyoD, and a significant activity effect was detected in soleus Mrf4. No main effects or interactions were observed in the EDL, but in the diaphragm, a significant activity effect was observed for Myf5 with EXER+DOX expressing higher levels than SED+DOX. Conclusion: Doxorubicin treatment increased soleus MRFs and exercise boosted MRF response in soleus and diaphragm suggesting that exercise may enhance regenerative signaling with DOX treatment. Level of evidence: I b, individual randomized controlled trial.

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Doxorubicin interacts directly with skinned single skeletal muscle fibres

Cited by 22 publications

References 8 publications

Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle

Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle

Rapid cooling-induced contractures in rat skinned skeletal muscle fibres originate from sarcoplasmic reticulum Ca2+ release through ryanodine and inositol trisphosphate receptors

Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression

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