Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

Shum, A.; Mahendradatta, T.; Taylor, Ryland J.; Painter, Arran; Moore, Melissa M.; Tsoli, Maria; Tan, Timothy C.; Clarke, Stephen; Robertson, Graham; Polly, Patsie

doi:10.18632/aging.100436

Cited by 69 publications

(75 citation statements)

References 34 publications

(48 reference statements)

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“…However, at the time point that we analyzed we did not observe any change in the expression of TGFβ or any of the family members that we considered, at least in our experimental model. Ultimately, based on our findings, the occurrence of muscle weakness following chemotherapy administration may well result from a combined effect associated with the reduction of mitochondrial content and the loss of sarcoplasmic/structural proteins, as also suggested by detecting thinner Z-lines and I-bands [51, 53]. …”

Section: Discussionmentioning

confidence: 89%

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

et al. 2016

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Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.

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Section: Discussionmentioning

confidence: 89%

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

et al. 2016

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“…Distorted mitochondria are present in muscle during cancer cachexia [13] and this is associated with loss of skeletal muscle structural integrity. Different research groups have shown that, in spite of the fact that the UCP2 gene is overexpressed in skeletal muscle from cachectic rats [14,15] and that muscle oxidative capacity -complex IV activity -is decreased, no alteration in either ATP synthesis or uncoupling are observed.…”

Section: Oxidative Damage and Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Myocyte Enhancer Factor (MEF) 2C, a myogenic transcription factor, is significantly downregulated in skeletal muscle from cachectic mice. Since MEF2C targets myozenin and myoglobin, it seems to be associated with deregulated oxygen transport capacity and ATP regeneration [13].…”

Section: Oxidative Damage and Mitochondrial Dysfunctionmentioning

confidence: 99%

Cachexia and sarcopenia: mechanisms and potential targets for intervention

Argilés

Busquets

Stemmler³

et al. 2015

Current Opinion in Pharmacology

242

162

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“…Several of the genes shared across multiple over-represented pathways have been previously studied in models of muscle wasting and cachectic patients including FOS [50,60], FoxO1 [50,61,62], IL-6 receptor (IL6Ra) [63,64], MEF2C [65] and p21 (CDKN1A) [66,67]. Of note, both extensively characterized E3-ligases, MuRF-1 (TRIM63) and Atrogin-1 (Fbxo32), were among the 147 overlapping genes (Supplemental Table 1) though only MuRF-1 was part of an over-represented pathway ( Figure 5C).…”

Section: Importance Of Cytokine and Immune Signaling Pathways In Thementioning

confidence: 99%

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

Tseng

Liva

Dauki

et al. 2017

Preprint

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BackgroundCancer cachexia impacts the majority of advanced cancer patients but no approved anticachexia therapeutic exits. Recent late stage clinical failures of anabolic anti-cachexia therapy revealed heterogeneous responses to anabolic therapies and a limited ability to translate improved body composition into functional benefit. It is currently unclear what governs anabolic responsiveness in cachectic patient populations. Methods We evaluated anabolic androgen therapy combined with the novel anti-cachectic histone deacetylase inhibitor (HDACi) AR-42 in a series of studies using the C-26 mouse model of experimental cachexia. The ability of treatment to suppress tumor-mediated catabolic signaling and promote anabolic effects were characterized. Results Anabolic anti-cachexia monotherapy with the selective androgen receptor modulator (SARM) GTx-024 or enobosarm had no impact on cachectic outcomes in the C-26 model. A minimally effective dose of AR-42 provided mixed anti-cachectic benefits when administered alone but when combined with GTx-024 significantly improved bodyweight (p <0.0001), hind limb muscle mass (p <0.05), and voluntary grip strength (p <0.0001) versus tumor bearing controls. Similar efficacy resulted from the combination of AR-42 with multiple androgens. Anti-cachectic efficacy was associated with the ability to reverse pSTAT3 and atrogene induction in gastrocnemius muscle of tumor-bearing animals in the absence of treatment-mediated changes in serum IL-6 or LIF. Conclusions Anabolic GTx-024 monotherapy is incapable of overcoming catabolic signaling in the C-26 model of experimental cachexia. Anti-cachectic androgen therapy is greatly improved by successful blockade of STAT3 mediated atrophy with AR-42. Combined androgen and HDAC inhibitor administration represents promising approach to improve anabolic response in cachectic patient populations.

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Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

Cited by 69 publications

References 34 publications

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

Cachexia and sarcopenia: mechanisms and potential targets for intervention

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

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