Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

Abstract

Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer-host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer-host interaction side of cancer cachexia, often overlooking the capability of chemotherapy to induce cachectic myopathy. Accumulating evidence in experimental models of cachexia suggests that some chemotherapeutic agents rapidly induce cachectic myopathy, although the underlying mechanisms responsible vary between agents. Importantly, we highlight the capacity of specific chemotherapeutic agents to induce cachectic myopathy, as not all chemotherapies have been evaluated for cachexia-inducing properties-alone or in clinically compatible regimens. Furthermore, we discuss the experimental evidence surrounding therapeutic strategies that have been evaluated in chemotherapy-induced cachexia models, with particular focus on exercise interventions and adjuvant therapeutic candidates targeted at the mitochondria.

Keywords: cachexia; chemotherapy; exercise therapy; mitoprotection; muscle wasting; myopathy; pharmaceutical adjuvants; skeletal muscle.

Figure 1

Known mechanisms of doxorubicin (DOX)-induced cachectic myopathy. DOX promotes reactive oxygen species (ROS) production primarily via Complex I dysfunction, which induces mitochondrial dysfunction and tumour-necrosis factor-α (TNF-α)-dependent inflammation, which can promote pyroptosis via increased nucleotide binding oligmerisation domain, leucine rich repeat-containing protein 3 (NLRP3) inflammasome formation, and activation of apoptotic caspases. This stimulates a regulation in the development and DNA damage response 1 (REDD1) transcription program, which overarches DOX-induced cachectic myopathy. DOX also reduces the replenishment of the satellite cell pool, which contributes to cachectic myopathy through impaired muscle repair. Underlying skeletal muscle wasting, DOX increases protein degradation via the ubiquitin-proteasomal system (UPS), autophagy, apoptotic caspases, and the calcium (Ca²⁺)-dependent proteases, calpains, while also reducing protein synthesis in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. While the exact mechanism has not been fully elucidated, endoplasmic reticulum (ER) stress or the unfolded protein response (UPR) signalling may be contributing factors. DOX also alters Ca²⁺ dynamics and promotes oxidative damage to myofibrillar proteins causing skeletal muscle dysfunction. Created with biorender.com (accessed on 6 July 2021).

Figure 2

Known mechanisms of cisplatin (cis-diamminedichloropaltinum(II) (CDDP))-induced cachectic myopathy. CDDP promotes reactive oxygen species (ROS) production potentially through: (1) increased peroxiredoxin (PRX) sulphonylation; and (2) inflammation induced by pro-inflammatory cytokine mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription program activation, which is a central mechanism of CDDP-induced cachectic myopathy. The underlying mechanism regulating CDDP-induced skeletal muscle wasting is increased protein degradation involving elevated ubiquitin-proteasomal system (UPS) activity and the promotion of macroautophagy. Additionally, there is evidence of reduced protein synthesis via mammalian target of rapamycin complex 1 (mTORC1)-dependent signalling cascades. CDDP induces skeletal muscle dysfunction through promoting aberrant calcium (Ca²⁺) dynamics and oxidative damage to myofibrillar proteins. Created with biorender.com (accessed on 6 July 2021).

Figure 3

(5FU)-related cachectic myopathy. 5FU monotherapy promotes the phosphorylation of atrophic regulators, p38 mitogen activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These mechanistic targets are likely to be stimulated via signalling modulators including reactive oxygen species (ROS). 5FU does induce a pro-fibrotic skeletal muscle microenvironment and reduces the expression of the key cytoskeletal proteins, desmin and dystrophin, which suggests that 5FU primes muscle for cachectic myopathy. Interestingly, when additional chemotoxic insult to skeletal muscle occurs alongside 5FU such as in 5FU combination regimens, the induction of cachectic myopathy is observed. This is underscored by increased ROS production that stimulates the phosphorylation of p38 MAPK and ERK1/2 alongside mitochondrial dysfunction, leading to skeletal muscle wasting and dysfunction. Created with biorender.com (accessed on 6 July 2021).

Figure 4

The impact of anti-cancer chemotherapy treatment on cachectic myopathy and possible protective therapeutic interventions. Broadly, chemotherapeutic agents used in clinical cancer treatment can both directly and indirectly target skeletal muscle through induction or amplification of systemic cachexia. The result is the initiation of a wasting and dysfunction program within skeletal muscle, involving: increased muscle protein degradation, reduced protein synthesis, mitochondrial dysfunction and oxidative stress, cytoskeletal disorganisation and reduction of key cytoskeletal proteins that stabilise the muscle membrane, pro-fibrotic signalling within the extracellular matrix, and altered calcium (Ca2+) dynamics. The result is muscle wasting and dysfunction that leaves patients weak and fatigued, which affects their capacity to undertake activities of daily living and reduces quality of life. Several potential therapeutic approaches are currently being investigated to protect against or treat these symptoms including appetite stimulants, activin receptor signalling inhibitors, nutritional supplements, and phytotherapies. Novel therapeutic strategies could include exercise and mitoprotective compounds (e.g., SS-31, BGP-15, dimethyl fumarate (DMF), epicatechin, and pterostilbene). Abbreviations: CNS AIR: central nervous system acute illness response. Created with biorender.com (accessed on 6 July 2021).