Abstract
Simple SummaryIn addition to cancer-related factors, anti-cancer chemotherapy treatment can drive life-threatening body wasting in a syndrome known as cachexia. Emerging evidence has described the impact of several key chemotherapeutic agents on skeletal muscle in particular, and the mechanisms are gradually being unravelled. Despite this evidence, there remains very little research regarding therapeutic strategies to protect muscle during anti-cancer treatment and current global grand challenges focused on deciphering the cachexia conundrum fail to consider this aspect—chemotherapy-induced myopathy remains very much on the dark side of the cachexia sphere. This review explores the impact and mechanisms of, and current investigative strategies to protect against, chemotherapy-induced myopathy to illuminate this serious issue.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.
Highlights
Chemotherapy constitutes a group of anti-neoplastic agents that were progressively discovered throughout the 19th century and became commonplace in oncological treatment as first-line or complementary therapeutic strategies for most cancer types [1]
In a mouse model of diabetes, MTX was shown to elicit benefits on skeletal muscle glucose metabolism [116,117]. These findings suggest that chemotherapeutic agents from the anti-metabolite class display a modest myotoxic profile compared to other chemotherapy classes
Research has predominately contextualised cancer cachexia as governed by tumour-related factors without considering the other side of the cachexia sphere—chemotherapy [9]. This is problematic with respect to the clinical compatibility of this paradigm, as the large majority of cancer patients typically receive chemotherapy as part of their treatment strategy
Summary
Chemotherapy constitutes a group of anti-neoplastic agents that were progressively discovered throughout the 19th century and became commonplace in oncological treatment as first-line or complementary therapeutic strategies for most cancer types [1]. Chemotherapy targets cell cycle arrest through DNA-damage pathways that promote apoptotic cell death, agents are heterogeneously stratified into different classes depending on their mode of action [2] Independent of their different mechanisms, chemotherapies remain effective at inducing cancer cytotoxicity to abate the hyper-active neoplastic cell cycle [3]. Chemotherapeutic agents reduce body mass concurrent with skeletal muscle atrophy and dysfunction (referred to as cachectic myopathy). These side-effects are clinically evident during patient deconditioning in the oncological setting [12], where weight loss and fatigue are two key debilitating events prominent in metabolic wasting syndrome, cachexia [13]. We discuss the challenges associated with current experimental approaches used to investigate chemotherapy-induced cachexia and adjuvant strategies to protect against it
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