Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia

Sirago, Giuseppe; Conte, Elena; Fracasso, Flavio; Cormio, Antonella; Fehrentz, Jean‐Alain; Martinez, Jean; Musicco, Clara; Camerino, Claudia; Fonzino, Adriano; Rizzi, Laura; Torsello, Antonio; Lezza, Angela Maria Serena; Liantonio, Antonella; Cantatore, Palmiro; Pesce, Vito

doi:10.1038/s41598-017-13504-y

Cited by 37 publications

(73 citation statements)

References 69 publications

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“…In animal models of cisplatin-induced cachexia, it has been shown that cisplatin treatment in fast-twitch skeletal muscle stimulated cell autophagy by decreasing the level of active Akt and therefore, phosphorylated FoxO3a, thus favoring its localization in the nucleus. Accordingly, a parallel upregulation of genes coding for autophagy proteins such as Beclin-1, a protein involved in autophagy starting, and LC3-II and p62 has also been observed [36]. A similar effect has been also associated to cisplatin in an in vitro study performed on C2C12 myotubes [37].…”

Section: Autophagy Pathwaymentioning

confidence: 78%

“…Indeed, levels of PGC-1α, NRF-1, and TFAM decreased in rats treated with cisplatin to an extent ranging from 30% to 50% compared to control animals. The change of PGC-1α might be due to the impairment of the PI3K-Akt-mTOR signaling pathway induced by cisplatin in this cachectic animal model [36]. Accordingly, changes in mtDNA levels were also observed [36].…”

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 83%

“…The change of PGC-1α might be due to the impairment of the PI3K-Akt-mTOR signaling pathway induced by cisplatin in this cachectic animal model [36]. Accordingly, changes in mtDNA levels were also observed [36]. Mitochondria are highly dynamic organelles that continuously change their morphology by fission and fusion.…”

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 91%

“…Particularly, TFAM is a mitochondrial protein controlling mtDNA maintenance and replication, as well as mitochondrial transcription [47,48]. Cisplatin treatment induced a decline of mitochondrial biogenesis and mitochondrial mass in rat tibialis anterioris (TA) muscle [36]. Indeed, levels of PGC-1α, NRF-1, and TFAM decreased in rats treated with cisplatin to an extent ranging from 30% to 50% compared to control animals.…”

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 99%

“…In particular, the phosphorylation at Ser-637 inhibits Drp1 activity thus preventing mitochondrial fission, whereas phosphorylation at Ser-616 activates Drp1 activity and induces mitochondrial fission [51]. Skeletal muscle fibers of cisplatin-treated animals are characterized by an increase of both fusion and fission proteins, with a prevalence of fission compared to fusion [36]. Indeed, a decrease in the level of Drp1 phosphorylated at S637 site has been observed, indicating an enhancement of fission activity of the protein leading to mitochondrial fragmentation, which is typically associated with atrophic muscles characterizing various metabolic disorders.…”

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 99%

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Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Conte

Bresciani

Rizzi

et al. 2020

IJMS

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Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.

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Section: Autophagy Pathwaymentioning

confidence: 78%

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 83%

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 91%

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 99%

Section: Mitochondrial Biogenesis and Dynamicmentioning

confidence: 99%

See 3 more Smart Citations

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Conte

Bresciani

Rizzi

et al. 2020

IJMS

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Growth hormone secretagogue receptor‐1a mediates ghrelin's effects on attenuating tumour‐induced loss of muscle strength but not muscle mass

Liu

Zhang

Lee

et al. 2021

J cachexia sarcopenia muscle

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Background Ghrelin may ameliorate cancer cachexia (CC) by preventing anorexia, muscle, and fat loss. However, the mechanisms mediating these effects are not fully understood. This study characterizes the pathways involved in muscle mass and strength loss in the Lewis lung carcinoma (LLC)-induced cachexia model, and the effects of ghrelin in mice with or without its only known receptor: the growth hormone secretagogue receptor-1a ((GHSR-1a), Ghsr +/+ and Ghsr À/À ). Methods Five to 7-month-old male C57BL/6J Ghsr +/+ and Ghsr À/À mice were inoculated with 1 × 10 6 heat-killed (HK) or live LLC cells (tumour implantation, TI). When tumours were palpable (7 days after TI), tumour-bearing mice were injected with vehicle (T + V) or ghrelin twice/day for 14 days (T + G, 0.8 mg/kg), while HK-treated mice were given vehicle (HK + V). Body weight and grip strength were evaluated before TI and at termination (21 days after TI). Hindlimb muscles were collected for analysis. Results Less pronounced body weight (BW) loss (87.70 ± 0.98% vs. 83.92 ± 1.23%, percentage of baseline BW in tumour-bearing Ghsr +/+ vs. Ghsr À/À , P = 0.008), and lower upregulation of ubiquitin-proteasome system (UPS, MuRF1/Trim63, 5.71 ± 1.53-fold vs. 9.22 ± 1.94-fold-change from Ghsr +/+ HK + V in tumour-bearing Ghsr +/+ vs. Ghsr -/-, P = 0.036) and autophagy markers (Becn1, Atg5, Atg7, tumour-bearing Ghsr +/+ < Ghsr À/À , all P < 0.02) were found in T + V Ghsr +/+ vs. Ghsr À/À mice. Ghrelin attenuated LLC-induced UPS marker upregulation in both genotypes, [Trim63 was decreased from 5.

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Loss of REDD1 prevents chemotherapy‐induced muscle atrophy and weakness in mice

Hain

Waning

2021

J cachexia sarcopenia muscle

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Background Chemotherapy is an essential treatment to combat solid tumours and mitigate metastasis. Chemotherapy causes side effects including muscle wasting and weakness. Regulated in Development and DNA Damage Response 1 (REDD1) is a stress‐response protein that represses the mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), and its expression is increased in models of muscle wasting. The aim of this study was to determine if deletion of REDD1 is sufficient to attenuate chemotherapy‐induced muscle wasting and weakness in mice. Methods C2C12 myotubes were treated with carboplatin, and changes in myotube diameter were measured. Protein synthesis was measured by puromycin incorporation, and REDD1 mRNA and protein expression were analysed in myotubes treated with carboplatin. Markers of mTORC1 signalling were measured by western blot. REDD1 global knockout mice and wild‐type mice were treated with a single dose of carboplatin and euthanized 7 days later. Body weight, hindlimb muscle weights, forelimb grip strength, and extensor digitorum longus whole muscle contractility were measured in all groups. Thirty minutes prior to euthanasia, mice were injected with puromycin to measure puromycin incorporation in skeletal muscle. Results C2C12 myotube diameter was decreased at 24 (P = 0.0002) and 48 h (P < 0.0001) after carboplatin treatment. Puromycin incorporation was decreased in myotubes treated with carboplatin for 24 (P = 0.0068) and 48 h (P = 0.0008). REDD1 mRNA and protein expression were increased with carboplatin treatment (P = 0.0267 and P = 0.0015, respectively), and this was accompanied by decreased phosphorylation of Akt T308 (P < 0.0001) and S473 (P = 0.0006), p70S6K T389 (P = 0.0002), and 4E‐binding protein 1 S65 (P = 0.0341), all markers of mTORC1 activity. REDD1 mRNA expression was increased in muscles from mice treated with carboplatin (P = 0.0295). Loss of REDD1 reduced carboplatin‐induced body weight loss (P = 0.0013) and prevented muscle atrophy in mice. REDD1 deletion prevented carboplatin‐induced decrease of protein synthesis (P = 0.7626) and prevented muscle weakness. Conclusions Carboplatin caused loss of body weight, muscle atrophy, muscle weakness, and inhibition of protein synthesis. Loss of REDD1 attenuates muscle atrophy and weakness in mice treated with carboplatin. Our study illustrates the importance of REDD1 in the regulation of muscle mass with chemotherapy treatment and may be an attractive therapeutic target to combat cachexia.

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Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia

Cited by 37 publications

References 69 publications

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Growth hormone secretagogue receptor‐1a mediates ghrelin's effects on attenuating tumour‐induced loss of muscle strength but not muscle mass

Loss of REDD1 prevents chemotherapy‐induced muscle atrophy and weakness in mice

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