The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

Abstract

Significance: The management of cancer patients is frequently complicated by the occurrence of a complex syndrome known as cachexia. It is mainly characterized by muscle wasting, a condition that associates with enhanced protein breakdown and with negative energy balance. While the mechanisms underlying cachexia have been only partially elucidated, understanding the pathogenesis of muscle wasting in cancer hosts is mandatory to design new targeted therapeutic strategies. Indeed, most of cancer patients will experience cachexia during the course of their disease, and about 25% of cancer-related deaths are due to this syndrome, rather than to the tumor itself. Recent Advances: Compelling evidence suggests that an altered redox homeostasis likely contributes to cancerinduced muscle protein depletion, directly or indirectly activating the intracellular degradative pathways. In addition, oxidative stress impinges on both mitochondrial number and function; the other way round, altered mitochondria lead to enhanced redox imbalance, creating a vicious loop that eventually results in negative energy metabolism. Critical Issues: The present review focuses on the possibility that pharmacological and nonpharmacological strategies able to restore a physiologic redox balance could be useful components of treatment schedules aimed at counteracting cancer-induced muscle wasting. Future Directions: Exercise and the use of exercise mimetic drugs represent the most promising approaches capable of reinforcing the muscle antioxidant defenses of cancer patients. The results from ongoing and new clinical trials are needed to validate the preclinical studies and provide effective therapies for cancer cachexia.

Impact of Rehabilitation on Breast Cancer Related Fatigue: A Pilot Study

“…The skeletal muscle system has been recently hypothesized to have a key role in fatigue pathogenesis (43,44). Furthermore, there are multiple examples in literature on the direct mitochondria damage, inducing a dysfunction characterized by an increased intracellular oxidative stress and low energy supply (8,(45)(46)(47)(48). Noteworthy, exercise training could remodel the mitochondrial network, influencing the mitochondria intrinsic plasticity through different mechanisms and modulating their shape in response to fission and fusion events (45,47,(49)(50)(51).…”

Redox tolerance and metabolic reprogramming in solid tumors

“…Tumor effects on host metabolism often cause a fatal wasting syndrome called cachexia that occurs in 50% of patients, and is experienced by 80% in advanced cancer patients (Biswas & Acharyya, 2020). This multi‐system syndrome, namely cachexia, reduces patient tolerance to therapy (surgical and medical interventions), increases therapy‐related adverse effects, worsens life quality, and increases the rate of mortality among cancer patients (Kidd et al, 2019; Penna et al, 2020) and accounts directly for ~22% of deaths from cancer (Flint et al, 2017). Due to the key functions exerted by an intact muscular system in movement, breathing, swallowing, and chewing, it is expected that the quality of life is dramatically reduced in patients developing cachexia.…”

“…This condition can occur before involving apparent signs of body weight loss and before the diagnosis of cachexia in cancer patients (Crawford et al, 2016). Muscle wasting is associated with the augmented breakdown of proteins and the negative balance of energy (Penna et al, 2020). A lower skeletal muscle mass indicates a higher systemic inflammatory response (Abbass et al, 2019).…”

“…NF‐κB activated by proinflammatory cytokines can cause hypercatabolism of muscle proteins by increasing the expression of ubiquitin ligases specific for muscles, such as MuRF1 and atrogin‐1. Protein depletion due to cancer can alter redox homeostasis within the muscular system (Penna et al, 2020). The ongoing loss in the skeletal muscular mass, called sarcopenia, can be measured by skeletal muscle index, calculated easily by computed tomography (CT) scan at the level of L3 vertebra (Papaconstantinou et al, 2020).…”

“…However, the duration of exercise before inoculation of tumor is positively related to the reduction of the severity of cachexia (Niels et al, 2020). Reinforcing the antioxidative system within the muscles in cancer patients can be strengthened mostly by exercise and using exercise mimetic agents (Penna et al, 2020). Evidence, however, for the efficacy of exercise in cancer patients is insufficient, requiring ongoing trials (Grande et al, 2015).…”