Silibinin Alleviates Muscle Atrophy Caused by Oxidative Stress Induced by Cisplatin through ERK/FoxO and JNK/FoxO Pathways

Chiang

J cachexia sarcopenia muscle

et al. 2022

Background Cisplatin (CP) is a widely used chemotherapeutic drug with subsequent adverse effects on different organs and tissues including skeletal muscle loss and atrophy as the most common clinical symptoms. The molecular mechanism of cisplatin‐induced muscle atrophy is not clearly understood. However, recent significant advances indicate that it is related to an imbalance in both the protein status and apoptosis. Capsaicin (CAP) is one of the major ingredients in chilli peppers. It is a valuable pharmacological agent with several therapeutic applications in controlling pain and inflammation with particular therapeutic potential in muscle atrophy. However, the mechanisms underlying its protective effects against cisplatin‐induced muscle loss and atrophy remain largely unknown. This study aims to investigate capsaicin's beneficial effects on cisplatin‐induced muscle loss and atrophy in vitro and in vivo. Methods The anti‐muscle‐atrophic effect of capsaicin on cisplatin‐induced muscle loss was investigated using in vivo and in vitro studies. By using the pretreatment model, pretreated capsaicin for 24 h and treated with cisplatin for 48 h, we utilized a C2C12 myotube formation model where cell viability analysis, immunofluorescence, and protein expression were measured to investigate the effect of capsaicin in hampering cisplatin‐induced muscle atrophy. C57BL/6 mice were administered capsaicin (10, 40 mg/kg BW) as a pretreatment for 5 weeks and cisplatin (3 mg/kg BW) for seven consecutively days to assess muscle atrophy in an animal model for protein and oxidative stress examination, and the grip strength was tested to evaluate the muscle strength. Results Our study results indicated that cisplatin caused lower cell viability and showed a subset of hallmark signs typically recognized during atrophy, including severe reduction in the myotube diameter, repression of Akt, and mTOR protein expression. However, pretreatment with capsaicin could ameliorate cisplatin‐induced muscle atrophy by up‐regulating the protein synthesis in skeletal muscle as well as down‐regulating the markers of protein degradation. Additionally, capsaicin was able to downregulate the protein expression of apoptosis‐related markers, activated TRPV1 and autophagy progress modulation and the recovery of lysosome function. In vivo, capsaicin could relieve oxidative stress and cytokine secretion while modulating autophagy‐related lysosome fusion, improving grip strength, and alleviating cisplatin‐induced body weight loss and gastrocnemius atrophy. Conclusions These findings suggest that capsaicin can restore cisplatin‐induced imbalance between protein synthesis and protein degradation pathways and it may have protective effects against cisplatin‐induced muscle atrophy.

Section: Resultsmentioning

confidence: 99%

Capsaicin alleviates cisplatin‐induced muscle loss and atrophy in vitro and in vivo

Chiang

J cachexia sarcopenia muscle

et al. 2022

“…Pharmacological targeting or gene knockdown of DUSP22 inhibited signaling by JNK (also known as stress-activated kinase) and FOXO3a (a key regulator of skeletal muscle atrophy). DUSP22 is also known as JNK-stimulating phosphatase 1 (JSP1) and JNK activation has been shown to promote FOXO3a activation in numerous cell types [19][20][21][22]. To confirm the ability of DUSP22 to stimulate JNK in this study, we showed that gene knockdown in skeletal muscle downregulated JNK and the downstream mediator, c-jun.…”

Section: Discussionmentioning

confidence: 67%

“…JNK signaling is increased in cancer-associated skeletal muscle loss and upregulates the atrogenes atrogin-1 (Fbxo32) MuRF-1 (Trim63) and [18]. JNK signaling has been shown to induce the activation of FOXO3a, which is a master regulator of skeletal muscle wasting and transcriptional activator of MuRF-1 and atrogin-1 [19][20][21][22]. Thus, JNK could be a drug target for this disorder.…”

Section: Introductionmentioning

confidence: 99%

Targeting phosphatase DUSP22 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression

Lee,

Kim,

Kim

et al. 2024

Preprint

Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or pharmacological inhibition prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

“…Cisplatin remains the most intensively studied individual compound [35][36][37][40][41][42][43][44][46][47][48]. Cisplatin suppresses protein synthesis via an Akt protein kinase B (Akt)-dependent mechanism, which leads to p70S6k1 dephosphorylation.…”

Section: Molecular Pathways Of Systemic Treatment-related Muscle Lossmentioning

confidence: 99%

Adverse effects of systemic cancer therapy on skeletal muscle: myotoxicity comes out of the closet

Klassen

Schiessel

Baracos

2023

Purpose of reviewSystemic cancer therapy-associated skeletal muscle wasting is emerging as a powerful impetus to the overall loss of skeletal muscle experienced by patients with cancer. This review explores the clinical magnitude and biological mechanisms of muscle wasting during systemic cancer therapy to illuminate this adverse effect. Emerging strategies for mitigation are also discussed.Recent findingsClinical findings include precise, specific measures of muscle loss over the course of chemotherapy, targeted therapy and immunotherapy. All these therapeutic classes associate with quantitatively important muscle loss, independent of tumor response. Parallel experimental studies provide understanding of the specific molecular basis of wasting, which can include inhibition of protein synthesis, proliferation and differentiation, and activation of inflammation, reactive oxygen species, autophagy, mitophagy, apoptosis, protein catabolism, fibrosis and steatosis in muscle. Strategies to mitigate these muscle-specific adverse effects of cancer therapy remain in the earliest stages of development.SummaryThe adverse side effect of cancer therapy on skeletal muscle has been largely ignored in the development of cancer therapeutics. Given the extent to which loss of muscle mass and function can bear on patients’ function and quality of life, protection/mitigation of these side effects is a research priority.