Protein homeostasis disruption in cisplatin-induced skeletal muscle atrophy: toxicological insights from experimental studies

Abstract

Cisplatin is a widely used platinum-based chemotherapeutic agent whose dose-limiting toxicities, including nephrotoxicity, neurotoxicity, and myelosuppression, have been extensively characterized. In contrast, skeletal muscle has not traditionally been regarded as a primary target of cisplatin toxicity. However, accumulating experimental evidence indicates that cisplatin administration leads to a significant reduction in skeletal muscle mass and fiber size, even in the absence of tumor burden or overt cachexia. These findings suggest that cisplatin itself can directly induce skeletal muscle atrophy as a form of drug-induced toxicity. Animal and cell-based studies have demonstrated that cisplatin activates catabolic signaling in skeletal muscle, most notably through enhanced protein degradation via the ubiquitin–proteasome system. This response is accompanied by increased expression of muscle-specific E3 ubiquitin ligases, including muscle RING finger 1 (MuRF1) and muscle atrophy F-box protein (MAFbx/atrogin-1), which are established mediators of skeletal muscle atrophy. In parallel, suppression of anabolic signaling, particularly impairment of the insulin-like growth factor-1/Akt/mechanistic target of rapamycin complex 1 (mTORC1) pathway, has been reported, indicating a shift in muscle protein turnover toward a catabolic state. Recent studies suggest that cellular stress responses, such as endoplasmic reticulum stress, may be involved in regulating these processes. This review summarizes experimental evidence supporting cisplatin-induced skeletal muscle atrophy and discusses the underlying toxicological processes from a muscle-centered perspective. By distinguishing drug-induced muscle toxicity from cancer cachexia and other wasting conditions, we propose that skeletal muscle should be recognized as a clinically relevant but underestimated target organ of cisplatin toxicity. Improved understanding of these processes may support the development of strategies to preserve muscle mass and function during cancer chemotherapy.

INTRODUCTION

Cisplatin is a platinum-based chemotherapeutic agent that has been used for several decades in the treatment of a broad range of solid tumors, including lung, testicular, ovarian, and head and neck cancers (Dasari and Tchounwou, 2014; Galluzzi et al., 2014). Owing to its strong antitumor activity, cisplatin-based chemotherapy has contributed substantially to improvements in patient survival and remains a key component of many standard treatment regimens (Pirker, 2014; Hellmann et al., 2016). At the same time, however, the clinical utility of cisplatin is frequently limited by systemic toxicities that adversely affect patient outcomes during treatment and in the post-therapeutic period (Elmorsy et al., 2024).

Among these adverse effects, skeletal muscle atrophy has increasingly been recognized as a clinically important complication of anticancer therapy. Loss of skeletal muscle mass is closely associated with impaired physical function, increased fatigue, and reduced tolerance to chemotherapy, leading to a marked decline in quality of life in patients with cancer (Xu and Liu, 2025). In addition, clinical studies have demonstrated that skeletal muscle depletion is associated with unfavorable prognosis, including reduced overall survival and increased treatment-related complications (Aversa et al., 2017; Huot et al., 2021; Shachar et al., 2016; Au et al., 2021). Notably, muscle wasting often persists after completion of chemotherapy (Sturgeon et al., 2019; Osaki et al., 2024), underscoring its relevance not only during active treatment but also in long-term cancer survivorship and supportive care.

For many years, muscle atrophy observed during cisplatin therapy was primarily attributed to indirect factors such as decreased food intake, body weight loss, and reduced physical activity caused by treatment-related malaise (Prado et al., 2008; Donohoe et al., 2011; Fearon et al., 2011). Although these factors clearly contribute to muscle loss, they do not fully explain the magnitude or specific features of skeletal muscle atrophy reported in experimental models and clinical observations (Sakai et al., 2014; Baracos et al., 2018). This limitation in the traditional view has prompted increasing interest in the possibility that cisplatin itself exerts direct effects on skeletal muscle tissue. While sharing common catabolic pathways with cancer cachexia and sarcopenia, cisplatin-induced muscle atrophy is distinguished by its pharmacological trigger and partial independence from tumor burden. Although several anticancer agents have been reported to affect skeletal muscle mass (Campelj et al., 2021; Novinger et al., 2025), the most consistent evidence from preclinical studies supports cisplatin as a potent activator of an intrinsic muscle catabolic program within skeletal muscle, even in the absence of tumor burden (Soga et al., 2026; Nanri et al., 2026).

Prior to the mid-2010s, skeletal muscle was scarcely considered a primary target of cisplatin toxicity. In 2014, our group provided experimental evidence that cisplatin alone could directly induce skeletal muscle atrophy independently of tumor burden and even when compared to body weight-matched controls receiving restricted food intake (Sakai et al., 2014), thereby establishing skeletal muscle as a previously unrecognized target of cisplatin toxicity. More recently, experimental studies using animal models and cultured skeletal muscle cells have begun to support this concept, shifting attention toward cisplatin-induced alterations in cellular stress responses and protein homeostasis within skeletal muscle. Nevertheless, the available literature remains fragmented, and an integrated framework linking historical developments, experimental evidence, and cellular mechanisms has not yet been fully established.

Advances in supportive care have improved management of major cisplatin-related toxicities, including myelosuppression, renal impairment, and gastrointestinal adverse events such as nausea/vomiting (Elmorsy et al., 2024; Sikking et al., 2024; Oh and Hong, 2025). However, skeletal muscle atrophy remains underrecognized in clinical practice and continues to be inadequately managed.

In this mini review, we outline the historical progression of research on cisplatin-induced skeletal muscle atrophy, summarize key experimental findings demonstrating direct myotoxic effects of cisplatin, and discuss current understanding of the cellular responses involved. We further discuss unresolved issues and future perspectives for developing supportive strategies to preserve skeletal muscle mass and prevent muscle loss during cisplatin-based chemotherapy. It should be noted that cisplatin-induced skeletal muscle atrophy is a multifactorial process involving diverse cellular mechanisms. In this mini review, we primarily focus on selected pathways related to protein homeostasis and cellular stress responses, while other mechanisms, including mitochondrial dysfunction and cell death processes such as apoptosis and ferroptosis, are not covered in detail. It should also be noted that many of the molecular mechanisms discussed in this review are not unique to cisplatin but are shared across various muscle-wasting conditions, including those induced by anticancer therapies. In this context, cisplatin can be regarded as a representative and well-characterized agent that robustly induces these responses (Fig. 1).

Fig. 1

Conceptual shift in the understanding of cisplatin-induced skeletal muscle atrophy. Schematic illustration depicting the shift in conceptual understanding of cisplatin-induced skeletal muscle atrophy. Traditionally, skeletal muscle atrophy during cisplatin treatment was primarily interpreted as a secondary consequence of systemic effects, such as reduced food intake, body weight loss, and decreased physical activity. However, accumulating experimental evidence has led to a revised framework in which skeletal muscle is recognized as a direct target of cisplatin toxicity. In this updated view, muscle atrophy arises not only from indirect systemic factors but also from direct myotoxic effects of cisplatin on skeletal muscle tissue. This conceptual shift highlights skeletal muscle as a clinically relevant target organ of cisplatin toxicity, with important implications for physical function, quality of life, treatment tolerance, and patient prognosis.

Unlike previous reviews broadly summarizing multiple mechanisms associated with cisplatin-associated muscle wasting (Xu and Liu, 2025), the present review specifically focuses on disruption of protein homeostasis and stress-responsive signaling pathways in cisplatin-induced skeletal muscle atrophy from a toxicological perspective. Although apoptosis- and ferroptosis-related alterations have also been reported in cisplatin-treated skeletal muscle (Wu et al., 2023; You, 2024), the currently available evidence remains relatively limited and mechanistically heterogeneous compared with studies focusing on protein homeostasis–related pathways. Therefore, the present review primarily focuses on stress-responsive signaling, anabolic suppression, and proteolytic regulation, which have been more consistently characterized in experimental models of cisplatin-induced skeletal muscle atrophy. Specifically, while apoptosis-related changes have been reported in cisplatin-treated skeletal muscle, the available studies vary considerably in the experimental conditions, cell types, and apoptotic markers examined, making it difficult to integrate these findings into a coherent mechanistic framework at this stage. Similarly, ferroptosis has been implicated in cisplatin-induced muscle atrophy in a limited number of studies, but the mechanistic relationship between ferroptotic cell death and the protein homeostasis–centered pathways that are the primary focus of this review has not been established. For these reasons, the present review does not attempt to provide an integrated discussion of these cell death pathways, and readers are referred to recent comprehensive reviews (Xu and Liu, 2025; Huang et al., 2025) for coverage of these topics.

ADVANCES IN CISPLATIN THERAPY AND THE UNRESOLVED ISSUE OF SKELETAL MUSCLE ATROPHY

The history of cisplatin predates its emergence as a chemotherapeutic agent. The compound was originally synthesized by Michele Peyrone in 1844, and its molecular structure was later established by Alfred Werner in 1893. For many years, cisplatin remained primarily a chemical curiosity, with little attention directed toward its biological or medical significance. This situation changed in the 1960s, when Rosenberg and colleagues unexpectedly observed that electrolysis products released from platinum electrodes suppressed cell division in Escherichia coli (Rosenberg et al., 1965). Subsequent characterization identified cis-dichlorodiammineplatinum (II), now known as cisplatin, as the active compound responsible for these effects. These findings initiated sustained interest in platinum coordination complexes as potential anticancer agents. Cisplatin soon distinguished itself by exhibiting strong antitumor activity across multiple cancer types, including testicular, ovarian, and head and neck cancers. By the late 1970s, cisplatin had become firmly established as a cornerstone of systemic therapy for germ cell malignancies, culminating in its approval by the U.S. Food and Drug Administration in 1978 (Kelland, 2007). This milestone not only secured cisplatin’s position in oncology but also stimulated broader exploration of metal-based anticancer drugs (Frezza et al., 2010).

Early research focused primarily on elucidating the antitumor mechanisms of cisplatin, particularly DNA adduct formation and the induction of cancer cell death (Rosenberg et al., 1969) (Jordan and Carmo-Fonseca, 2000). During this period, toxic effects on non-tumor tissues were largely regarded as unavoidable consequences of effective chemotherapy. Cisplatin exerts its antitumor effects primarily through binding to DNA and forming intra- and interstrand crosslinks, thereby disrupting DNA replication and transcription (Dasari and Tchounwou, 2014). In addition to nuclear DNA, cisplatin has also been reported to affect mitochondrial DNA, potentially contributing to mitochondrial dysfunction (Yang et al., 2014). Furthermore, accumulating evidence suggests that cisplatin may also interact with proteins, indicating that its molecular targets extend beyond genomic DNA (Frezza et al., 2010).

From the 1990s onward, accumulating clinical experience enabled extensive characterization of dose-limiting toxicities, including nephrotoxicity, neurotoxicity, and gastrointestinal adverse effects. This growing awareness prompted the development of supportive strategies such as hydration protocols, antiemetic regimens, and dose-modification approaches (Alberts and Noel, 1995; Barabas et al., 2008; Crona et al., 2017). Historically, nephrotoxicity and gastrointestinal toxicity have been considered the most critical adverse effects of cisplatin, followed by neurotoxicity and ototoxicity as cumulative, dose-dependent toxicities (Fig. 2).

Fig. 2

Historical development of cisplatin adverse effects and the emergence of skeletal muscle atrophy as an underrecognized but clinically relevant toxicity. Timeline summarizing key milestones in the history of cisplatin, from its initial synthesis and structural characterization to its clinical application and the progressive recognition of its adverse effects. Early research primarily focused on antitumor efficacy, followed by the identification of classical dose-limiting toxicities, including nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity, and myelosuppression. In contrast, skeletal muscle atrophy has only recently been recognized as an underappreciated but clinically relevant adverse effect, particularly in the context of long-term cancer survivorship and functional outcomes.

By contrast, skeletal muscle atrophy has only recently emerged as an underrecognized but clinically relevant adverse effect, particularly in long-term cancer survivors. In earlier studies, muscle loss was rarely considered a primary outcome and was instead interpreted as a secondary consequence of malnutrition, reduced physical activity, or overall disease burden. This perception gradually shifted as improvements in cancer treatment led to a growing population of long-term survivors. With increasing emphasis on post-treatment quality of life and physical function, skeletal muscle atrophy emerged as a persistent and clinically meaningful complication, contributing to fatigue, reduced exercise capacity, and prolonged functional impairment even after cessation of chemotherapy (Prado et al., 2008; Goedendorp et al., 2012; Fearon et al., 2011).

Experimental studies demonstrated that skeletal muscle atrophy during cisplatin treatment cannot be fully explained by indirect systemic factors alone, leading to a conceptual shift. Animal studies have shown that cisplatin administration induces muscle mass reduction even when compared with control animals whose body weights were maintained at comparable levels through dietary restriction (Sakai et al., 2014; Sakai et al., 2017). These findings suggested that cisplatin may directly target skeletal muscle tissue rather than acting solely through secondary systemic effects (Fig. 1).

Subsequent in vitro studies reinforced this interpretation. Exposure of cultured skeletal muscle cells to cisplatin induced the expression of muscle atrophy–related genes, including muscle RING finger 1 (MuRF1) and muscle atrophy F-box protein (MAFbx/atrogin-1), and activated protein degradation pathways in the absence of hormonal or nutritional changes (Sakai et al., 2014). Together, these observations established a new research framework in which skeletal muscle is recognized as a direct cellular target of cisplatin toxicity. However, existing studies remain heterogeneous in terms of experimental models, muscle types, and pathways examined, highlighting the need for an integrated synthesis of the accumulating evidence.

EXPERIMENTAL EVIDENCE FOR CISPLATIN-INDUCED SKELETAL MUSCLE ATROPHY

In vivo evidence from animal models

The first experimental evidence supporting a direct contribution of cisplatin to skeletal muscle atrophy was obtained from animal studies in which the drug was administered independently of tumor burden. These studies demonstrated significant reductions in skeletal muscle mass and muscle fiber diameters even in otherwise healthy animals. Importantly, muscle atrophy was observed in the absence of overt cachexia, indicating that cisplatin itself plays an active role in the development of muscle wasting. Subsequent investigations refined these findings by controlling for confounding factors such as food intake and physical activity. Dietary restriction experiments and short-term dosing protocols demonstrated that cisplatin-induced muscle loss could not be fully explained by reduced caloric intake alone. Under these controlled conditions, cisplatin consistently reduced muscle weight and disrupted muscle morphology, further supporting the concept of a direct myotoxic effect (Sakai et al., 2014).

At the molecular level, in vivo studies have reported increased expression of genes involved in muscle protein degradation pathways, particularly components of the ubiquitin–proteasome system. Cisplatin administration increases ubiquitin and ubiquitinated proteins and enhances proteasome-mediated degradation in skeletal muscle (Sakai et al., 2020; Sakai et al., 2022b; Sato et al., 2023). In parallel, expression of muscle-specific E3 ubiquitin ligases, such as MuRF1 and atrogin-1, is consistently upregulated (Sakai et al., 2014). These catabolic changes are accompanied by suppression of anabolic signaling, as exogenous administration of insulin-like growth factor-1 (IGF-1) attenuates cisplatin-induced muscle loss and restores Akt signaling in mice (Sakai et al., 2021). A recent review further emphasizes that cisplatin disrupts skeletal muscle protein homeostasis through enhanced proteolysis combined with impaired anabolic signaling (Xu and Liu, 2025).

In vitro evidence from cultured muscle cells

Complementary evidence for direct cisplatin effects has been obtained from in vitro studies using cultured myotubes. In differentiated C2C12 myotubes, cisplatin induces morphological features of atrophy, including reduced myotube diameter, together with alterations in proteolytic systems and signaling pathways in the absence of systemic influences (Fanzani et al., 2011). Similar models demonstrate dysregulation of protein homeostasis under cisplatin exposure, supporting a cell-autonomous effect (Le Bacquer et al., 2024). At the transcriptional level, cisplatin increases the expression of atrophy-related genes and stress-responsive factors at clinically relevant concentrations. In addition, cisplatin induces multiple cellular stress responses, including mitochondrial dysfunction and altered redox balance (Matsumoto et al., 2022; Chi et al., 2022; Sato et al., 2024). Although the relative contribution of each stress response varies among experimental systems, their combined activation indicates that cisplatin imposes multifaceted cellular stress on skeletal muscle cells. Beyond effects on differentiated myotubes, cisplatin has also been shown to inhibit myogenic differentiation of C2C12 myoblasts. Downregulation of SPARC-like protein 1 (SPARCL1) was identified as a key molecular event in this process, indicating that cisplatin may directly impair muscle regenerative capacity at the level of myogenic progenitor cells (Sakai et al., 2022a).

Collectively, in vivo and in vitro findings provide converging evidence that skeletal muscle is a direct target of cisplatin toxicity, forming the basis for investigations into the cellular stress mechanisms linking cisplatin exposure to muscle atrophy.

PROTEOLYTIC SYSTEMS INVOLVED IN CISPLATIN-INDUCED SKELETAL MUSCLE ATROPHY

Activation of the ubiquitin–proteasome pathway

Accumulating evidence indicates that activation of proteolytic systems is a central event in cisplatin-induced skeletal muscle atrophy. Among these systems, the ubiquitin–proteasome pathway (UPP) represents the principal machinery responsible for selective degradation of myofibrillar proteins in skeletal muscle, and its involvement has been well established across a wide range of atrophic conditions (Taillandier et al., 2004; Rom and Reznick, 2016; Haberecht-Müller et al., 2021). In experimental models, cisplatin administration consistently increases the expression of muscle-specific E3 ubiquitin ligases, most notably MuRF1 and atrogin-1, both of which are widely accepted mediators and molecular markers of muscle atrophy (Sakai et al., 2014; Sakai et al., 2020; Wu et al., 2019). The upregulation of these ligases is accompanied by enhanced ubiquitination of structural muscle proteins, supporting the view that cisplatin accelerates proteasome-dependent protein breakdown rather than inducing nonspecific protein loss. Together, these findings support the concept that cisplatin exerts a direct myotoxic effect that converges on canonical proteolytic pathways.

At the transcriptional level, expression of MuRF1 and atrogin-1 is largely governed by forkhead box Os (FoxOs) transcription factors, which function as central regulators of muscle protein turnover (Sandri et al., 2004; Lecker et al., 2004). Under physiological conditions, FoxOs activity is restrained by insulin/IGF-1–Akt signaling through phosphorylation-dependent cytoplasmic retention. Cisplatin disrupts this regulatory axis by suppressing Akt signaling, resulting in reduced FoxOs phosphorylation and enhanced nuclear localization of FoxOs proteins (Zhang et al., 2020; Bae et al., 2021). Consequently, transcription of FoxOs target genes involved in proteolysis is derepressed, leading to coordinated induction of the atrophy program.

Importantly, this signaling cascade closely resembles the canonical muscle-wasting response observed in other catabolic states, including fasting, denervation, and glucocorticoid exposure (Sandri et al., 2004; Lecker et al., 2004; Sakai et al., 2019). These findings suggest that cisplatin-induced muscle atrophy reflects activation of regulatory pathways that normally control muscle mass under stress, rather than a unique or atypical mechanism.

Contribution of autophagy–lysosome signaling

In addition to the ubiquitin–proteasome pathway, autophagy–lysosome signaling has also been implicated in cisplatin-induced skeletal muscle atrophy. Several experimental studies have reported upregulation of autophagy-related genes together with increased accumulation of LC3-II in skeletal muscle following cisplatin administration, suggesting activation of the autophagic machinery. These changes have been observed across different experimental models and muscle types, supporting the notion that autophagy is a consistent component of the muscle response to cisplatin exposure (Stacchiotti et al., 2014; Conte et al., 2020; Seo et al., 2021). However, the functional significance of autophagy activation in this context remains incompletely understood. A key unresolved issue is whether autophagy acts as a direct contributor to muscle wasting or instead represents a secondary, stress-adaptive response aimed at preserving cellular homeostasis. On the one hand, excessive or dysregulated autophagy may accelerate the degradation of myofibrillar components and organelles, thereby exacerbating muscle loss. On the other hand, moderate induction of autophagy is generally considered cytoprotective, facilitating the removal of damaged proteins and dysfunctional mitochondria generated by cisplatin-induced oxidative and endoplasmic reticulum (ER) stress.

Adding further complexity, some studies indicate that cisplatin disrupts autophagy flux rather than simply enhancing autophagy initiation. Impaired lysosomal function or defective autophagosome–lysosome fusion has been reported following cisplatin treatment, resulting in accumulation of LC3-II and autophagic vesicles without efficient substrate clearance (Sakai et al., 2020). Under such conditions, apparent “activation” of autophagy markers may reflect stalled or incomplete autophagy, potentially converting an initially protective response into a maladaptive process. Taken together, these findings suggest that autophagy–lysosome signaling in cisplatin-treated skeletal muscle is tightly regulated and context dependent. The balance between adaptive autophagy and autophagy-associated muscle loss is likely influenced by factors such as cisplatin dose, treatment duration, muscle fiber composition, and the coexistence of other stress pathways (Xia et al., 2021). Clarifying the temporal dynamics and functional consequences of autophagy modulation will be essential for determining whether this pathway represents a viable therapeutic target in the prevention of cisplatin-induced muscle atrophy.

Interplay between proteolytic systems and cellular stress

Protein degradation in skeletal muscle is strongly influenced by cellular stress responses, including oxidative stress and ER stress. Oxidative stress has been shown to promote muscle protein breakdown through activation of atrophy-related transcriptional programs. Early studies demonstrated that reactive oxygen species stimulate the expression of muscle-specific ubiquitin ligases and other components of proteolytic systems, thereby accelerating the degradation of myofibrillar proteins (Li et al., 1998; Li and Reid, 2000). Cisplatin is well recognized as an inducer of oxidative stress in multiple tissues, and similar increases in oxidative stress markers have also been reported in skeletal muscle following cisplatin administration (Matsumoto et al., 2022). These findings suggest that oxidative stress contributes, at least in part, to the shift toward a catabolic state in skeletal muscle during cisplatin treatment.

ER stress responses represent another important regulatory input into muscle protein homeostasis. Activation of the unfolded protein response (UPR) occurs in response to impaired protein folding within the ER and influences not only protein quality control but also the expression of genes involved in protein degradation and autophagy. Previous studies have shown that ER stress signaling can induce components of the ubiquitin–proteasome system as well as autophagy-related genes in skeletal muscle (Ogata et al., 2006; Ebert et al., 2020). Consistent with these observations, recent evidence indicates that cisplatin induces ER stress in skeletal muscle, as reflected by changes in canonical UPR markers (Soga et al., 2026; Nanri et al., 2026). Despite evidence implicating both oxidative stress and ER stress, their coordinated roles in regulating proteolytic systems during cisplatin-induced muscle atrophy remain insufficiently characterized. These stress pathways are known to be closely interconnected: oxidative stress can exacerbate protein misfolding and ER stress, whereas sustained UPR activation may further disturb redox balance. Such interactions may contribute to prolonged activation of proteolytic pathways, including the ubiquitin–proteasome system and autophagy–lysosome signaling (Fig. 3). However, studies that simultaneously evaluate oxidative stress, ER stress, and downstream proteolytic responses in cisplatin-treated skeletal muscle are still limited. In addition, most existing work has focused on enhanced protein degradation, whereas the impact of these stress responses on translational capacity and protein synthesis has received less attention. ER stress is known to suppress global protein synthesis through translational control mechanisms, and oxidative stress may further impair anabolic signaling. How suppression of protein synthesis interacts with increased proteolysis over the course of cisplatin treatment, and how this balance ultimately determines muscle loss, remain important open questions. In addition to these pathways, regulated cell death processes, including apoptosis and ferroptosis, have also been implicated in cisplatin-induced muscle atrophy. In particular, cisplatin-induced mitochondrial damage may be closely associated with impaired energy metabolism in skeletal muscle (Sato et al., 2024). However, their precise roles remain to be fully elucidated and are not the primary focus of this review.

Fig. 3

Proposed cellular pathways underlying cisplatin-induced skeletal muscle atrophy. Cisplatin exposure induces multiple cellular stress responses in skeletal muscle, including ER stress, oxidative stress, and mitochondrial dysfunction. These stress signals converge on catabolic signaling pathways, leading to activation of the ubiquitin–proteasome system and upregulation of muscle-specific E3 ubiquitin ligases, such as MuRF1 and atrogin-1, through FoxOs-dependent transcriptional programs. In parallel, autophagy–lysosome signaling is modulated, although its functional contribution to muscle loss remains incompletely defined. Suppression of anabolic signaling, including the IGF-1/Akt pathway, further shifts the balance toward net protein loss, resulting in reduced muscle mass, decreased fiber diameter, and impaired physical function. These effects have been observed in experimental models independent of tumor burden.

Collectively, the available evidence supports a model in which cisplatin imposes stress on multiple intracellular targets in skeletal muscle cells, including nuclear DNA, mitochondrial components, and possibly proteins, thereby initiating upstream stress responses such as oxidative stress and ER stress (Frezza et al., 2010; Yang et al., 2014; Soga et al., 2026; Nanri et al., 2026). These stress signals converge on downstream effector pathways: suppression of IGF-1/Akt–mTORC1 anabolic signaling and transcriptional activation of FoxO-dependent proteolytic programs, leading to coordinated induction of MuRF1, atrogin-1, and autophagy-related genes (Sakai et al., 2021; Bae et al., 2021; Conte et al., 2020). The net result is a shift in muscle protein homeostasis toward catabolism, manifesting as reduced muscle mass and fiber atrophy (Fig. 3). It should be noted, however, that the precise sequence and relative contribution of each upstream stress signal remain incompletely characterized. In particular, whether ER stress acts as a primary driver or a secondary amplifier of the catabolic response, and how oxidative stress and ER stress interact in a temporally coordinated manner during cisplatin exposure, are questions that have not yet been fully resolved in skeletal muscle. Direct experimental evidence linking each upstream trigger to specific downstream proteolytic outputs in a causally defined manner is still limited, and much of the proposed mechanistic framework remains inferential at this stage.

MODIFYING FACTORS AND THERAPEUTIC PERSPECTIVES

Regulation of anabolic–catabolic balance

The balance between protein synthesis and degradation is a central determinant of skeletal muscle mass (Glass, 2003). Cisplatin disrupts this balance by simultaneously suppressing anabolic signaling and enhancing proteolytic activity. In particular, inhibition of the insulin-like growth factor-1 (IGF-1)/Akt pathway has been repeatedly observed following cisplatin treatment and is considered a key event that predisposes skeletal muscle to a catabolic state. Under such conditions, even relatively modest reductions in anabolic drive can have disproportionate effects on muscle mass, especially when proteolytic pathways are already activated.

Experimental evidence supports a contributory role of impaired anabolic signaling in cisplatin-induced skeletal muscle atrophy. Cisplatin has been reported to reduce IGF-1 expression in skeletal muscle, and attenuation of this local IGF-1 signaling is considered to participate in the development of muscle atrophy (Sakai et al., 2021). In vivo administration of exogenous IGF-1 attenuates cisplatin-induced reductions in muscle mass and restores Akt phosphorylation. In addition, IGF-1 treatment suppresses the cisplatin-induced upregulation of the muscle-specific E3 ubiquitin ligases MuRF1 and atrogin-1, suggesting that restoration of anabolic signaling can inhibit catabolic responses at the transcriptional level (Sakai et al., 2021) (Fig. 3). Together, these findings indicate that, in cisplatin-treated skeletal muscle, anabolic and catabolic pathways are not regulated independently but are closely coordinated. Beyond enhanced protein degradation, suppression of protein synthesis may also contribute to the development of muscle atrophy during cisplatin treatment. Attenuation of IGF-1/Akt signaling is expected to impair downstream translational control mediated by mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of muscle protein synthesis. While direct measurements of translational capacity in cisplatin-treated skeletal muscle remain limited, reduced activation of upstream anabolic signaling pathways suggests that protein synthesis is likely compromised, at least to some extent. Importantly, even partial suppression of anabolic signaling may synergize with increased proteolysis to accelerate muscle loss. Rather than acting as isolated processes, decreased protein synthesis and enhanced protein degradation likely operate in parallel, reinforcing one another over the course of cisplatin exposure. Further studies directly assessing muscle protein synthesis, together with proteolytic activity, will be necessary to clarify the relative contribution of impaired translational capacity to cisplatin-induced skeletal muscle atrophy.

Therapeutic perspectives and emerging modulators

The beneficial effects of exercise are likely multifactorial and may involve not only myokine-mediated signaling but also systemic hormonal responses (e.g., glucocorticoids and other endocrine adaptations), metabolic adaptations, and modulation of inflammatory pathways. Exercise-based interventions represent a promising non-pharmacological strategy, as muscle contraction suppresses atrophy-related gene expression and supports protein synthesis. Experimental studies suggest that exercise partially counteracts cisplatin-induced muscle loss without compromising antitumor efficacy (Hojman et al., 2014; Sakai et al., 2017; Seo et al., 2021; Xu and Liu, 2025). Nutritional support may further enhance these effects, although it is unlikely to be sufficient alone (Paddon-Jones et al., 2008; Deutz et al., 2014). In addition to exercise itself, growing attention has focused on exercise-induced myokines as potential modulators of chemotherapy-induced muscle wasting. Irisin, a cleavage product of fibronectin type III domain containing 5 (FNDC5), is released from skeletal muscle in response to physical activity and has been implicated in the regulation of muscle metabolism, mitochondrial function, redox balance, and cognitive function (Boström et al., 2012; Zhang et al., 2022; Chen et al., 2022). Notably, cisplatin-induced muscle wasting has been shown to suppress irisin synthesis and secretion in skeletal muscle (Miyauchi et al., 2025). This reduction in circulating irisin has also been speculated to contribute to chemotherapy-associated cognitive impairment (so-called “chemo-brain”). Collectively, these findings raise the possibility that irisin may link exercise-mediated protection of skeletal muscle with the modulation of neurocognitive complications during cisplatin treatment, although further studies are required to clarify its precise role.

Pharmacological and nutritional interventions targeting upstream regulators of proteolytic signaling have also been reported (Huang et al., 2025). Bioactive compounds such as dihydromyricetin, silibinin, daidzein, eicosapentaenoic acid, and capsaicin attenuate cisplatin-induced muscle atrophy by modulating redox-sensitive signaling and suppressing FoxOs-dependent induction of E3 ubiquitin ligases (You, 2024; Chi et al., 2022; Zhang et al., 2021; Ikeno et al., 2022; Huang et al., 2023). Additional approaches targeting protein homeostasis and myogenic capacity, including cannabidiol, Kampo medicines, and functional nutritional products, have shown efficacy in experimental models (Hong et al., 2021; Sekine et al., 2025; Yeh et al., 2025; Zhong et al., 2022). However, the precise mechanisms underlying these protective effects often remain unclear.

Future directions

Based on the experimental evidence reviewed in the present article, a tentative hierarchical classification of the molecular mechanisms underlying cisplatin-induced skeletal muscle atrophy can be proposed. Activation of the ubiquitin–proteasome system, upregulation of MuRF1 and atrogin-1, and suppression of IGF-1/Akt signaling represent mechanisms that are broadly shared across various muscle-wasting conditions, including cancer cachexia and sarcopenia, and are therefore not unique to cisplatin. However, cisplatin appears to engage these common catabolic pathways through relatively specific upstream triggers. In particular, ER stress–associated suppression of anabolic signaling and cisplatin-induced transcriptional alterations in stress-responsive genes in skeletal muscle have been more consistently reported for cisplatin than for other cytotoxic anticancer agents, such as 5-fluorouracil, irinotecan, cyclophosphamide, and vincristine, in tumor-independent experimental models (Soga et al., 2026; Nanri et al., 2026). Regarding other platinum-based agents, direct evidence for oxaliplatin- or carboplatin-induced skeletal muscle atrophy in tumor-independent models remains limited, and whether the mechanisms identified for cisplatin extend to other platinum compounds cannot be determined from currently available data. Taken together, the available evidence suggests that cisplatin-induced skeletal muscle atrophy shares downstream catabolic effectors with other wasting conditions but is distinguished by the nature and combination of upstream stress signals, particularly ER stress and direct myotoxic effects in the absence of tumor burden. This tentative positioning is based on currently available evidence and should be refined as comparative studies across anticancer agents and platinum compounds accumulate.

Based on the mechanisms discussed in this review, several key directions for future research can be identified. First, further studies are needed to clarify how proteolytic systems, including the ubiquitin–proteasome pathway and autophagy–lysosome signaling, are coordinately regulated under cisplatin-induced cellular stress conditions. In particular, the temporal relationship between activation of stress responses (e.g., ER stress and oxidative stress) and induction of proteolytic pathways remains to be fully elucidated. Second, the relative contribution of impaired protein synthesis versus enhanced protein degradation in determining net muscle loss during cisplatin treatment should be quantitatively assessed. Although suppression of anabolic signaling has been reported, direct measurements of translational capacity in skeletal muscle remain limited. Third, comparative studies between cisplatin and other platinum-based agents, as well as other anticancer drugs, will be necessary to refine the tentative hierarchical classification proposed in this review. Future studies should particularly focus on clarifying how cellular stress responses, including ER stress and oxidative stress, are integrated with proteolytic systems and anabolic signaling pathways to regulate muscle protein homeostasis in cisplatin-treated skeletal muscle, thereby providing a mechanistic basis for targeted therapeutic interventions.

CONCLUSION AND OUTLOOK

Cisplatin-induced skeletal muscle atrophy has emerged as an underrecognized but clinically relevant adverse effect of chemotherapy. Experimental evidence indicates that cisplatin directly activates muscle catabolic programs, with enhanced protein degradation via the ubiquitin–proteasome pathway as a major mechanism. This proteolytic dominance is reinforced by suppression of anabolic signaling and by systemic modifiers during treatment. While accelerated protein degradation is a central feature, emerging evidence suggests that impaired protein synthesis may also contribute to cisplatin-induced muscle atrophy, highlighting the need for integrated analyses of muscle protein turnover. Future studies should also address additional mechanisms, including mitochondrial dysfunction and regulated cell death pathways, to achieve a more comprehensive understanding of cisplatin-induced skeletal muscle toxicity.

From a clinical perspective, substantial progress has been made in the management of major cisplatin-associated toxicities, such as bone marrow suppression, nephrotoxicity, and gastrointestinal adverse effects (Elmorsy et al., 2024; Sikking et al., 2024; Oh and Hong, 2025). In contrast, skeletal muscle atrophy remains largely overlooked, with no standardized strategy currently available for its prevention or treatment. Addressing this gap may be critical for preserving physical function and improving long-term outcomes in cancer survivors. From a toxicological perspective, skeletal muscle should be recognized as a relevant target tissue in cisplatin exposure. Muscle atrophy compromises physical function and quality of life and may influence treatment tolerance and long-term outcomes. Addressing this adverse effect will require integrated strategies combining exercise, nutritional support, and selective modulation of catabolic signaling. Continued investigation into cisplatin-induced skeletal muscle atrophy may provide a foundation for rational supportive care strategies and contribute to improving outcomes for patients receiving cisplatin-based chemotherapy.

ACKNOWLEDGMENTS

The authors are grateful to members of the Departments of Toxicology and Biomolecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, for their valuable input.

Funding

This work was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (grant number 22K06869) and Hoshi University Otani Research Grants 2022.

Conflict of interest

The authors declare that there is no conflict of interest.

Data availability

The data in this study are included in the article/supplementary materials. Contact the corresponding author(s) directly to request the underlying data.

Author contributions

Conceptualization: Hiroyasu Sakai

Funding acquisition: Hiroyasu Sakai, Kumiko Ogawa

Supervision: Author Kumiko Ogawa

Visualization: Hiroyasu Sakai

Writing – original draft: Hiroyasu Sakai

Writing – review & editing: Risako Kon, Nobutomo Ikarashi, Kumiko Ogawa

Ethical approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

REFERENCES

•  Alberts,  D.S. and  Noel,  J.K. (1995): Cisplatin-associated neurotoxicity: can it be prevented? Anticancer Drugs, 6, 369-383.
•  Au,  P.C.,  Li,  H.L.,  Lee,  G.K.,  Li,  G.H.,  Chan,  M.,  Cheung,  B.M.,  Wong,  I.C.,  Lee,  V.H.,  Mok,  J.,  Yip,  B.H.,  Cheng,  K.K.,  Wu,  C.H. and  Cheung,  C.L. (2021): Sarcopenia and mortality in cancer: A meta-analysis. Osteoporos. Sarcopenia, 7 (Suppl 1), S28-S33.
•  Aversa,  Z.,  Costelli,  P. and  Muscaritoli,  M. (2017): Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther. Adv. Med. Oncol., 9, 369-382.
•  Bae,  J.H.,  Seo,  D.Y.,  Lee,  S.H.,  Shin,  C.,  Jamrasi,  P.,  Han,  J. and  Song,  W. (2021): Effects of exercise on AKT/PGC1-α/FOXO3a pathway and muscle atrophy in cisplatin-administered rat skeletal muscle. Korean J. Physiol. Pharmacol., 25, 585-592.
•  Barabas,  K.,  Milner,  R.,  Lurie,  D. and  Adin,  C. (2008): Cisplatin: a review of toxicities and therapeutic applications. Vet. Comp. Oncol., 6, 1-18.
•  Baracos,  V.E.,  Martin,  L.,  Korc,  M.,  Guttridge,  D.C. and  Fearon,  K.C. (2018): Cancer-associated cachexia. Nat. Rev. Dis. Primers, 4, 17105.
•  Boström,  P.,  Wu,  J.,  Jedrychowski,  M.P.,  Korde,  A.,  Ye,  L.,  Lo,  J.C.,  Rasbach,  K.A.,  Boström,  E.A.,  Choi,  J.H.,  Long,  J.Z.,  Kajimura,  S.,  Zingaretti,  M.C.,  Vind,  B.F.,  Tu,  H.,  Cinti,  S.,  Højlund,  K.,  Gygi,  S.P. and  Spiegelman,  B.M. (2012): A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481, 463-468.
•  Campelj,  D.G.,  Goodman,  C.A. and  Rybalka,  E. (2021): Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere. Cancers (Basel), 13, 3615.
•  Chen,  K.,  Wang,  K. and  Wang,  T. (2022): Protective effect of irisin against Alzheimer’s disease. Front. Psychiatry, 13, 967683.
•  Chi,  M.Y.,  Zhang,  H.,  Wang,  Y.X.,  Sun,  X.P.,  Yang,  Q.J. and  Guo,  C. (2022): Silibinin Alleviates Muscle Atrophy Caused by Oxidative Stress Induced by Cisplatin through ERK/FoxO and JNK/FoxO Pathways. Oxid. Med. Cell. Longev., 2022, 5694223.
•  Conte,  E.,  Bresciani,  E.,  Rizzi,  L.,  Cappellari,  O.,  De Luca,  A.,  Torsello,  A. and  Liantonio,  A. (2020): Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies. Int. J. Mol. Sci., 21, 1242.
•  Crona,  D.J.,  Faso,  A.,  Nishijima,  T.F.,  McGraw,  K.A.,  Galsky,  M.D. and  Milowsky,  M.I. (2017): A Systematic Review of Strategies to Prevent Cisplatin-Induced Nephrotoxicity. Oncologist, 22, 609-619.
•  Dasari,  S. and  Tchounwou,  P.B. (2014): Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol., 740, 364-378.
•  Deutz,  N.E.,  Bauer,  J.M.,  Barazzoni,  R.,  Biolo,  G.,  Boirie,  Y.,  Bosy-Westphal,  A.,  Cederholm,  T.,  Cruz-Jentoft,  A.,  Krznariç,  Z.,  Nair,  K.S.,  Singer,  P.,  Teta,  D.,  Tipton,  K. and  Calder,  P.C. (2014): Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group. Clin. Nutr., 33, 929-936.
•  Donohoe,  C.L.,  Ryan,  A.M. and  Reynolds,  J.V. (2011): Cancer cachexia: mechanisms and clinical implications. Gastroenterol. Res. Pract., 2011, 601434.
•  Ebert,  S.M.,  Bullard,  S.A.,  Basisty,  N.,  Marcotte,  G.R.,  Skopec,  Z.P.,  Dierdorff,  J.M.,  Al-Zougbi,  A.,  Tomcheck,  K.C.,  DeLau,  A.D.,  Rathmacher,  J.A.,  Bodine,  S.C.,  Schilling,  B. and  Adams,  C.M. (2020): Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ. J. Biol. Chem., 295, 2787-2803.
•  Elmorsy,  E.A.,  Saber,  S.,  Hamad,  R.S.,  Abdel-Reheim,  M.A.,  El-Kott,  A.F.,  AlShehri,  M.A.,  Morsy,  K.,  Salama,  S.A. and  Youssef,  M.E. (2024): Advances in understanding cisplatin-induced toxicity: molecular mechanisms and protective strategies. Eur. J. Pharm. Sci., 203, 106939.
•  Fanzani,  A.,  Zanola,  A.,  Rovetta,  F.,  Rossi,  S. and  Aleo,  M.F. (2011): Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and subsequent increment activity of proteasome and autophagy systems. Toxicol. Appl. Pharmacol., 250, 312-321.
•  Fearon,  K.,  Strasser,  F.,  Anker,  S.D.,  Bosaeus,  I.,  Bruera,  E.,  Fainsinger,  R.L.,  Jatoi,  A.,  Loprinzi,  C.,  MacDonald,  N.,  Mantovani,  G.,  Davis,  M.,  Muscaritoli,  M.,  Ottery,  F.,  Radbruch,  L.,  Ravasco,  P.,  Walsh,  D.,  Wilcock,  A.,  Kaasa,  S. and  Baracos,  V.E. (2011): Definition and classification of cancer cachexia: an international consensus. Lancet Oncol., 12, 489-495.
•  Frezza,  M.,  Hindo,  S.,  Chen,  D.,  Davenport,  A.,  Schmitt,  S.,  Tomco,  D. and  Dou,  Q.P. (2010): Novel metals and metal complexes as platforms for cancer therapy. Curr. Pharm. Des., 16, 1813-1825.
•  Galluzzi,  L.,  Vitale,  I.,  Michels,  J.,  Brenner,  C.,  Szabadkai,  G.,  Harel-Bellan,  A.,  Castedo,  M. and  Kroemer,  G. (2014): Systems biology of cisplatin resistance: past, present and future. Cell Death Dis., 5, e1257.
•  Glass,  D.J. (2003): Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat. Cell Biol., 5, 87-90.
•  Goedendorp,  M.M.,  Andrykowski,  M.A.,  Donovan,  K.A.,  Jim,  H.S.,  Phillips,  K.M.,  Small,  B.J.,  Laronga,  C. and  Jacobsen,  P.B. (2012): Prolonged impact of chemotherapy on fatigue in breast cancer survivors: a longitudinal comparison with radiotherapy-treated breast cancer survivors and noncancer controls. Cancer, 118, 3833-3841.
•  Haberecht-Müller,  S.,  Krüger,  E. and  Fielitz,  J. (2021): Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation. Biomolecules, 11, 1327.
•  Hellmann,  M.D.,  Li,  B.T.,  Chaft,  J.E. and  Kris,  M.G. (2016): Chemotherapy remains an essential element of personalized care for persons with lung cancers. Ann. Oncol., 27, 1829-1835.
•  Hojman,  P.,  Fjelbye,  J.,  Zerahn,  B.,  Christensen,  J.F.,  Dethlefsen,  C.,  Lonkvist,  C.K.,  Brandt,  C.,  Gissel,  H.,  Pedersen,  B.K. and  Gehl,  J. (2014): Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice. PLoS One, 9, e109030.
•  Hong,  M.,  Han,  I.H.,  Choi,  I.,  Cha,  N.,  Kim,  W.,  Kim,  S.K. and  Bae,  H. (2021): Magnoliae Cortex Alleviates Muscle Wasting by Modulating M2 Macrophages in a Cisplatin-Induced Sarcopenia Mouse Model. Int. J. Mol. Sci., 22, 3188.
•  Huang,  K.C.,  Chiang,  Y.F.,  Ali,  M. and  Hsia,  S.M. (2025): Cisplatin-Induced Muscle Wasting and Atrophy: Molecular Mechanism and Potential Therapeutic Interventions. J. Cachexia Sarcopenia Muscle, 16, e13817.
•  Huang,  K.C.,  Chiang,  Y.F.,  Huang,  T.C.,  Chen,  H.Y.,  Lin,  P.H.,  Ali,  M. and  Hsia,  S.M. (2023): Capsaicin alleviates cisplatin-induced muscle loss and atrophy in vitro and in vivo. J. Cachexia Sarcopenia Muscle, 14, 182-197.
•  Huot,  J.R.,  Pin,  F. and  Bonetto,  A. (2021): Muscle weakness caused by cancer and chemotherapy is associated with loss of motor unit connectivity. Am. J. Cancer Res., 11, 2990-3001.
•  Ikeno,  Y.,  Inomata,  M.,  Tsukimura,  Y.,  Suzuki,  Y.,  Takeuchi,  H.,  Harada,  Y.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Yamada,  T.,  Kamei,  J. and  Sakai,  H. (2022): Eicosapentaenoic acid suppresses cisplatin-induced muscle atrophy by attenuating the up-regulated gene expression of ubiquitin. J. Nutr. Biochem., 103, 108953.
•  Jordan,  P. and  Carmo-Fonseca,  M. (2000): Molecular mechanisms involved in cisplatin cytotoxicity. Cell. Mol. Life Sci., 57, 1229-1235.
•  Kelland,  L. (2007): The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer, 7, 573-584.
•  Le Bacquer,  O.,  Sanchez,  P.,  Patrac,  V.,  Rivoirard,  C.,  Saroul,  N.,  Giraudet,  C.,  Kocer,  A. and  Walrand,  S. (2024): Cannabidiol protects C2C12 myotubes against cisplatin-induced atrophy by regulating oxidative stress. Am. J. Physiol. Cell Physiol., 326, C1226-C1236.
•  Lecker,  S.H.,  Jagoe,  R.T.,  Gilbert,  A.,  Gomes,  M.,  Baracos,  V.,  Bailey,  J.,  Price,  S.R.,  Mitch,  W.E. and  Goldberg,  A.L. (2004): Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J., 18, 39-51.
•  Li,  Y.P. and  Reid,  M.B. (2000): NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes. Am. J. Physiol. Regul. Integr. Comp. Physiol., 279, R1165-R1170.
•  Li,  Y.P.,  Schwartz,  R.J.,  Waddell,  I.D.,  Holloway,  B.R. and  Reid,  M.B. (1998): Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J., 12, 871-880.
•  Matsumoto,  C.,  Sekine,  H.,  Nahata,  M.,  Mogami,  S.,  Ohbuchi,  K.,  Fujitsuka,  N. and  Takeda,  H. (2022): Role of Mitochondrial Dysfunction in the Pathogenesis of Cisplatin-Induced Myotube Atrophy. Biol. Pharm. Bull., 45, 780-792.
•  Miyauchi,  Y.,  Soga,  S.,  Nanri,  H.,  Yonamine,  S.,  Ogiwara,  T.,  Kiyama,  M.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Hosoe,  T. and  Sakai,  H. (2025): Decreased Expression and Secretion of the Myokine Fndc5/Irisin by Cisplatin Treatment in Mouse Skeletal Muscle. Calcif. Tissue Int., 116, 96.
•  Nanri,  H.,  Sakai,  H.,  Soga,  S.,  Chigusa,  Y.,  Ichikawa,  R.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y. and  Ogawa,  K. (2026): Cisplatin-associated transcriptional changes in ER stress-related genes in skeletal muscle and C2C12 myotubes. Toxicol. Mech. Methods, 36, 698-706.
•  Novinger,  L.J.,  Weinzierl,  N.M. and  Bonetto,  A. (2025): Diversity in chemotherapy-induced cachexia. Am. J. Physiol. Cell Physiol., 328, C139-C147.
•  Ogata,  M.,  Hino,  S.,  Saito,  A.,  Morikawa,  K.,  Kondo,  S.,  Kanemoto,  S.,  Murakami,  T.,  Taniguchi,  M.,  Tanii,  I.,  Yoshinaga,  K.,  Shiosaka,  S.,  Hammarback,  J.A.,  Urano,  F. and  Imaizumi,  K. (2006): Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol., 26, 9220-9231.
•  Oh,  J.J. and  Hong,  S.K. (2025): Contemporary management of metastatic urothelial carcinoma. Investig. Clin. Urol., 66, 375-382.
•  Osaki,  K.,  Fukushima,  T.,  Suzuki,  K.,  Kamimura,  A.,  Yanai,  S. and  Morishita,  S. (2024): Current status of research on sarcopenia in post-treatment cancer survivors in Japan:A narrative review. Fukushima J. Med. Sci., 70, 119-131.
•  Paddon-Jones,  D.,  Short,  K.R.,  Campbell,  W.W.,  Volpi,  E. and  Wolfe,  R.R. (2008): Role of dietary protein in the sarcopenia of aging. Am. J. Clin. Nutr., 87, 1562S-1566S.
•  Pirker,  R. (2014): Adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. Transl. Lung Cancer Res., 3, 305-310.
•  Prado,  C.M.,  Lieffers,  J.R.,  McCargar,  L.J.,  Reiman,  T.,  Sawyer,  M.B.,  Martin,  L. and  Baracos,  V.E. (2008): Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol., 9, 629-635.
•  Rom,  O. and  Reznick,  A.Z. (2016): The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass. Free Radic. Biol. Med., 98, 218-230.
•  Rosenberg,  B.,  Vancamp,  L. and  Krigas,  T. (1965): Inhibition of Cell Division in Escherichia Coli by Electrolysis Products from a Platinum Electrode. Nature, 205, 698-699.
•  Rosenberg,  B.,  VanCamp,  L.,  Trosko,  J.E. and  Mansour,  V.H. (1969): Platinum compounds: a new class of potent antitumour agents. Nature, 222, 385-386.
•  Sakai,  H.,  Asami,  M.,  Naito,  H.,  Kitora,  S.,  Suzuki,  Y.,  Miyauchi,  Y.,  Tachinooka,  R.,  Yoshida,  S.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y. and  Kamei,  J. (2021): Exogenous insulin-like growth factor 1 attenuates cisplatin-induced muscle atrophy in mice. J. Cachexia Sarcopenia Muscle, 12, 1570-1581.
•  Sakai,  H.,  Ikeno,  Y.,  Tsukimura,  Y.,  Inomata,  M.,  Suzuki,  Y.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Yamada,  T. and  Kamei,  J. (2020): Upregulation of ubiquitinated proteins and their degradation pathway in muscle atrophy induced by cisplatin in mice. Toxicol. Appl. Pharmacol., 403, 115165.
•  Sakai,  H.,  Kimura,  M.,  Isa,  Y.,  Yabe,  S.,  Maruyama,  A.,  Tsuruno,  Y.,  Kai,  Y.,  Sato,  F.,  Yumoto,  T.,  Chiba,  Y. and  Narita,  M. (2017): Effect of acute treadmill exercise on cisplatin-induced muscle atrophy in the mouse. Pflugers Arch., 469, 1495-1505.
•  Sakai,  H.,  Kimura,  M.,  Tsukimura,  Y.,  Yabe,  S.,  Isa,  Y.,  Kai,  Y.,  Sato,  F.,  Kon,  R.,  Ikarashi,  N.,  Narita,  M.,  Chiba,  Y. and  Kamei,  J. (2019): Dexamethasone exacerbates cisplatin-induced muscle atrophy. Clin. Exp. Pharmacol. Physiol., 46, 19-28.
•  Sakai,  H.,  Sagara,  A.,  Arakawa,  K.,  Sugiyama,  R.,  Hirosaki,  A.,  Takase,  K.,  Jo,  A.,  Sato,  K.,  Chiba,  Y.,  Yamazaki,  M.,  Matoba,  M. and  Narita,  M. (2014): Mechanisms of cisplatin-induced muscle atrophy. Toxicol. Appl. Pharmacol., 278, 190-199.
•  Sakai,  H.,  Suzuki,  Y.,  Miyauchi,  Y.,  Sato,  F.,  Ando,  Y.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Kamei,  J. and  Hosoe,  T. (2022a): Downregulation of Sparc-like protein 1 during cisplatin-induced inhibition of myogenic differentiation of C2C12 myoblasts. Biochem. Pharmacol., 204, 115234.
•  Sakai,  H.,  Zhou,  Y.,  Miyauchi,  Y.,  Suzuki,  Y.,  Ikeno,  Y.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Hosoe,  T. and  Kamei,  J. (2022b): Increased 20S Proteasome Expression and the Effect of Bortezomib during Cisplatin-Induced Muscle Atrophy. Biol. Pharm. Bull., 45, 910-918.
•  Sandri,  M.,  Sandri,  C.,  Gilbert,  A.,  Skurk,  C.,  Calabria,  E.,  Picard,  A.,  Walsh,  K.,  Schiaffino,  S.,  Lecker,  S.H. and  Goldberg,  A.L. (2004): Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell, 117, 399-412.
•  Sato,  K.,  Miyauchi,  Y.,  Xu,  X.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Hosoe,  T. and  Sakai,  H. (2023): Platinum-based anticancer drugs-induced downregulation of myosin heavy chain isoforms in skeletal muscle of mouse. J. Pharmacol. Sci., 152, 167-177.
•  Sato,  K.,  Satoshi,  Y.,  Miyauchi,  Y.,  Sato,  F.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Hosoe,  T. and  Sakai,  H. (2024): Downregulation of PGC-1α during cisplatin-induced muscle atrophy in murine skeletal muscle. Biochim. Biophys. Acta Mol. Basis Dis., 1870, 166877.
•  Sekine,  H.,  Matsumoto,  C.,  Fujitsuka,  N.,  Mogami,  S.,  Ohnishi,  S. and  Takeda,  H. (2025): Hochuekkito accelerates recovery from cisplatin induced-muscle atrophy accompanied by slow-twitch fiber-specific microRNA upregulation in mice. Front. Pharmacol., 16, 1502563.
•  Seo,  D.Y.,  Bae,  J.H.,  Zhang,  D.,  Song,  W.,  Kwak,  H.B.,  Heo,  J.W.,  Jung,  S.J.,  Yun,  H.R.,  Kim,  T.N.,  Lee,  S.H.,  Kim,  A.H.,  Jeong,  D.H.,  Kim,  H.K. and  Han,  J. (2021): Effects of cisplatin on mitochondrial function and autophagy-related proteins in skeletal muscle of rats. BMB Rep., 54, 575-580.
•  Shachar,  S.S.,  Williams,  G.R.,  Muss,  H.B. and  Nishijima,  T.F. (2016): Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review. Eur. J. Cancer, 57, 58-67.
•  Sikking,  C.,  Niggebrugge-Mentink,  K.L.,  van der Sman,  A.S.,  Smit,  R.H.,  Bouman-Wammes,  E.W.,  Beex-Oosterhuis,  M.M. and  van Kesteren,  C. (2024): Hydration Methods for Cisplatin Containing Chemotherapy: A Systematic Review. Oncologist, 29, e173-e186.
•  Soga,  S.,  Nanri,  H.,  Sakai,  H.,  Ichikawa,  R.,  Chigusa,  Y.,  Urase,  Y.,  Yonamine,  S.,  Ogiwara,  T.,  Kon,  R.,  Ikarashi,  N.,  Chiba,  Y.,  Hosoe,  T. and  Ogawa,  K. (2026): Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy. J. Toxicol. Sci., 51, 123-130.
•  Stacchiotti,  A.,  Rovetta,  F.,  Ferroni,  M.,  Corsetti,  G.,  Lavazza,  A.,  Sberveglieri,  G. and  Aleo,  M.F. (2014): Taurine rescues cisplatin-induced muscle atrophy in vitro: a morphological study. Oxid. Med. Cell. Longev., 2014, 840951.
•  Sturgeon,  K.M.,  Mathis,  K.M.,  Rogers,  C.J.,  Schmitz,  K.H. and  Waning,  D.L. (2019): Cancer- and Chemotherapy-Induced Musculoskeletal Degradation. JBMR Plus, 3, e10187.
•  Taillandier,  D.,  Combaret,  L.,  Pouch,  M.N.,  Samuels,  S.E.,  Béchet,  D. and  Attaix,  D. (2004): The role of ubiquitin-proteasome-dependent proteolysis in the remodelling of skeletal muscle. Proc. Nutr. Soc., 63, 357-361.
•  Wu,  C.T.,  Liao,  J.M.,  Ko,  J.L.,  Lee,  Y.L.,  Chang,  H.Y.,  Wu,  C.H. and  Ou,  C.C. (2019): D-Methionine Ameliorates Cisplatin-Induced Muscle Atrophy via Inhibition of Muscle Degradation Pathway. Integr. Cancer Ther., 18, 1534735419828832.
•  Wu,  Y.,  Pi,  D.,  Zhou,  S.,  Wang,  W.,  Ye,  H.,  Yi,  Z.,  Chen,  Y. and  Ouyang,  M. (2023): Yiqi Chutan Formula Reverses Cisplatin-Induced Apoptosis and Ferroptosis of Skeletal Muscle by Alleviating Oxidative Stress. Integr. Cancer Ther., 22, 15347354231172117.
•  Xia,  Q.,  Huang,  X.,  Huang,  J.,  Zheng,  Y.,  March,  M.E.,  Li,  J. and  Wei,  Y. (2021): The Role of Autophagy in Skeletal Muscle Diseases. Front. Physiol., 12, 638983.
•  Xu,  M. and  Liu,  X. (2025): Cisplatin-Induced Skeletal Muscle Atrophy: Biomolecular Mechanisms and the Protective Role of Exercise-Induced Myokines. Biomolecules, 15, 1495.
•  Yang,  Y.,  Liu,  H.,  Liu,  F. and  Dong,  Z. (2014): Mitochondrial dysregulation and protection in cisplatin nephrotoxicity. Arch. Toxicol., 88, 1249-1256.
•  Yeh,  S.L.,  Chen,  P.Y.,  Liao,  J.W.,  Huang,  R.L.,  Yu,  S.H.,  Chen,  L.N.,  Lee,  M.H.,  Chen,  L.W.,  Chen,  H.W.,  Yang,  Y.C.,  Wu,  Y.L. and  Liu,  K.L. (2025): The Protective Effects of Perch Essence Against Muscle Atrophy in Cancer Cachexia and Cisplatin Treatment. Curr. Issues Mol. Biol., 47, 152.
•  You,  L. (2024): Dihydromyricetin Inhibits Ferroptosis to Attenuate Cisplatin-Induced Muscle Atrophy. Physiol. Res., 73, 405-413.
•  Zhang,  H.,  Chi,  M.,  Chen,  L.,  Sun,  X.,  Wan,  L.,  Yang,  Q. and  Guo,  C. (2020): Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway. Front. Pharmacol., 11, 598166.
•  Zhang,  H.,  Chi,  M.,  Chen,  L.,  Sun,  X.,  Wan,  L.,  Yang,  Q. and  Guo,  C. (2021): Daidzein alleviates cisplatin-induced muscle atrophy by regulating Glut4/AMPK/FoxO pathway. Phytother. Res., 35, 4363-4376.
•  Zhang,  H.,  Wu,  X.,  Liang,  J.,  Kirberger,  M. and  Chen,  N. (2022): Irisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process. Ageing Res. Rev., 80, 101680.
•  Zhong,  R.,  Yang,  W.,  Li,  G.,  Xie,  S.,  Guo,  X.,  Zhou,  J.,  Ren,  B. and  Zhu,  Y. (2022): Nomegestrol acetate ameliorated adipose atrophy in a rat model of cisplatin-induced cachexia. Exp. Ther. Med., 25, 24.