Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and subsequent increment activity of proteasome and autophagy systems

Fanzani, Alessandro; Zanola, Alessandra; Rovetta, Francesca; Rossi, Stefania; Aleo, Maria Francesca

doi:10.1016/j.taap.2010.11.003

Cited by 63 publications

(62 citation statements)

References 62 publications

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“…Small ubiquitin-like modifier (SUMO) demodification, mediated by Senp3, is specifically associated with regulation of ribosome biogenesis (16). Gabarap is a known atrophy gene (24) and is upregulated in cisplatin-induced atrophy of C2C12 myotubes (9). Eukaryotic initiation factor 5a (Eif5a) undergoes a unique posttranslational modification (hypusination) that correlates with embryonic myogenic differentiation, and inhibition of EIF5A hypusination impairs C2C12 differentiation (33).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of gastrocnemius of “minimuscle” mice

Burniston

Meek

Pandey

et al. 2013

Physiological Genomics

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Few studies have investigated heterogeneity of selection response in replicate lines subjected to equivalent selection. We developed four replicate lines of mice based on high levels of voluntary wheel running (high runner or HR lines) while also maintaining four nonselected control lines. This led to the unexpected discovery of the HR minimuscle (HRmini) phenotype, recognized by a 50% reduction in hindlimb muscle mass, which became fixed in 1 of the four HR selected lines. Here, we report genome-wide expression profiling describing transcriptome differences between HRnormal and HRmini medial gastrocnemius. Consistent with the known reduction of type IIB fibers in HRmini, Myh4 gene expression was Ϫ8.82-fold less (P ϭ 0.0001) in HR mini, which was closely associated with differences in the "calcium signaling" canonical pathway, including structural genes (e.g., Mef2c, twofold greater in HRmini, P ϭ 0.0003) and myogenic factors (e.g., Myog, 3.8-fold greater in HR mini, P ϭ 0.0026) associated with slow-type myofibers. The gene that determines the HRmini phenotype is known to reside in a 2.6335-Mb interval on mouse chromosome 11 and 7 genes (Myh10, Chrnb1, Acadvl, Senp3, Gabarap, Eif5a, and Clec10a) from this region were differentially expressed. Verification by real-time PCR confirmed 1.5-fold greater (P Ͻ 0.05) expression of very long chain acyl-CoA dehydrogenase (Acadvl) in HRmini. Ten other genes associated with fatty acid metabolism were also upregulated in HRmini, suggesting differences in the ability to metabolize fatty acids in HRnormal and HRmini muscles. This work provides a resource for understanding differences in muscle phenotypes in populations exhibiting high running capacity. artificial selection; experimental evolution; wheel running ARTIFICIAL SELECTION EXPERIMENTS allow the study of evolution in real time and may reveal genetic correlations with the trait under selection. For example, selection of mice for enhanced protein content produced a hypermuscular phenotype (42) that subsequently was found to be caused by a deletion in myostatin (40). We (37) initiated artificial selection for increased wheelrunning behavior to investigate the evolution of locomotor behavior and physiological capacities for exercise in outbred house mice (Mus domesticus). After 10 generations of selection, individuals from the four replicate high-runner (HR) lines ran, on average, 70% more revolutions/day, and exhibited significantly greater (12%) maximal oxygen uptake (V O 2max ) compared with mice from four nonselected control lines (38). The differential in daily wheel running eventually plateaued at approximately ϩ200% compared with control lines, and at generation 49 the endurance capacity of HR lines during forced treadmill exercise was found to be 35% greater than control lines based on total distance run prior to exhaustion (30). Moreover, the endurance running capacity of HR mice (30) was significantly greater than reported in studies using direct genetic manipulations or pharmacological approaches to alter endura...

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling of gastrocnemius of “minimuscle” mice

Burniston

Meek

Pandey

et al. 2013

Physiological Genomics

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“…CisPt was dissolved in 1.5% DMSO to obtain 5 mM stock solution and administered to cells for 4 h up to 24 h at 10 or 50 μ M as previously reported [4]. Control experiments were conducted in parallel with equivalent amount of DMSO.…”

Section: Methodsmentioning

confidence: 99%

“…C2C12 myoblasts were seeded on round coverslides (13 mm diameter) and induced to differentiate as previously [4]. After CisPt treatment cell culture was fixed for 20 min in 4% paraformaldehyde in PBS and permeabilized for 5 min with 0.1% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

“…In particular we demonstrated that CisPt, through Akt pathway impairment, behaved as a potent trigger to cause atrophy via ubiquitin-proteasome and autophagy-lysosome systems [4–6]. In skeletal muscle, macroautophagy, called hereafter autophagy, is considered a compensatory mechanism to eliminate abnormal proteins and organelles in order to maintain mass and prolong longevity [7, 8].…”

Section: Introductionmentioning

confidence: 99%

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Taurine Rescues Cisplatin-Induced Muscle Atrophy In Vitro: A Morphological Study

Stacchiotti

Rovetta

Ferroni

et al. 2014

Oxidative Medicine and Cellular Longevity

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Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 μM CisPt challenged myotubes (4 h–8 h) before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Differently, 25 mM taurine pretreatment rescues the majority of myotubes size upon 50 μM CisPt at 24 h. Taurine appears to counteract atrophy by restoring regular microtubular apparatus and mitochondria and reducing the overload and the localization of autophagolysosomes. Such a promising taurine action in preventing atrophy needs further molecular and biochemical studies to best define its impact on muscle homeostasis and the maintenance of an adequate skeletal mass in vivo.

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“…It is also an antineoplastic drug that causes an array of adverse effects on various organs and tissues (3). Nephrotoxicity is one of the major side-effects of cisplatin chemotherapy (4) limiting the promising efficacy of cisplatin (5).…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 and type III collagen alterations in the heart of rats following cisplatin-induced toxicity

Huang

Liu

2011

Mol Med Report

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Abstract. Cisplatin-induced heart damage is associated with enzymes and protein alterations. The purpose of this study was to investigate cisplatin-induced alterations in cardiac endothelin (ET)-1 and type III collagen following administration of cisplatin. Male Wistar rats were randomly divided into two groups: a control and a cisplatin group. The cisplatin group received cisplatin intraperitoneally (i.p.) at a single dose of 7 mg/kg on day 6, while the controls were given the same amount of saline via the same route. On day 11, the rats were anesthetized and a thoracotomy was performed on all animals. Immunohistochemical analysis was performed to evaluate the protein expression of ET-1 and type III collagen. Sections were analyzed by digital image analysis. Results showed that the cardiac protein expression of ET-1 and type III collagen was altered following cisplatin-induced toxicity in rats. The expression of ET-1 and type III collagen was significantly increased after cisplatin treatment, supported by integrated optical density, when compared to the control group (P<0.05). The present findings indicate that such alterations may be reflected in abnormal cardiac function. Additionally, the proteins identified in this study may benefit investigations into the mechanisms underlying cisplatin-induced toxicity, thereby providing the necessary evidence for further research. IntroductionCisplatin is a chemotherapeutic agent widely used to treat a variety of solid tumors (1,2). It is also an antineoplastic drug that causes an array of adverse effects on various organs and tissues (3). Nephrotoxicity is one of the major side-effects of cisplatin chemotherapy (4) limiting the promising efficacy of cisplatin (5). Cisplatin-based chemotherapy also has a variety of vascular side-effects (6). Acute administration of cisplatin induces nausea/emesis and diarrhea (7). Chronic cisplatin may induce an enteric neuropathy characterized by changes in myenteric neurons associated with marked gastrointestinal motor dysfunction (7). Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections (8).Cisplatin-induced toxicity is known to be involved in the changes of antioxidant enzymes (GST, SOD, CAT, GSH-Px and GSH), serum superoxide dismutase (SOD), glutathione (GSH), malondiethylaldehyde (MDA), nitric oxide (NO) (9) and DNA (2,10). However, little is known about the changes in endothelin (ET)-1 and type III collagen expression in the heart following cisplatin-induced toxicity.The present study used immunohistochemical analysis to evaluate the expression of ET-1 and type III collagen in the heart, and to determine whether or not the protein expression is altered with cisplatin-induced toxicity. Materials and methodsAnimals and study design. Sixteen healthy adult male Wistar rats, weighing 210-250 g, were used in this study. The animals were housed individually in stainless-steel wire-bottomed cages in an air-conditione...

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Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and subsequent increment activity of proteasome and autophagy systems

Cited by 63 publications

References 62 publications

Gene expression profiling of gastrocnemius of “minimuscle” mice

Gene expression profiling of gastrocnemius of “minimuscle” mice

Taurine Rescues Cisplatin-Induced Muscle Atrophy In Vitro: A Morphological Study

Endothelin-1 and type III collagen alterations in the heart of rats following cisplatin-induced toxicity

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