Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

Abstract

Cancer cachexia is a debilitating syndrome mainly characterized by muscle and fat wasting, leading to the progressive loss of body weight and complicating the management of cancer patient. In particular, the loss of muscle weight is a negative prognostic factor, being associated with chemotherapy toxicity and reduced survival. Increased inflammation and protein dysmetabolism are some of the impairments that lead to muscle wasting in cancer patients. Together with these alterations, tumor growth and chemotherapy administration may affect mitochondrial function, impinging on the muscle energy metabolism. Indeed, therapeutic approaches poised to correct both hypercatabolism and mitochondrial alterations could be effective in preventing cancer-induced muscle wasting. Among the non-pharmacological approaches, exercise training is one of the best modulator of muscle physiology able to impinge on both protein and energy metabolism. However, the wasting phenotype that characterizes cancer patients could be not compatible with physical training, prompting the development of different strategies to improve muscle metabolism. The aim of this mini-review is to discuss both the beneficial effects and the limitations of exercise training in cancer cachexia and the adoption of drugs able to modulate exercise-induced pathways.

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

“…Beyond the regulation of the mitochondrial biogenesis, PGC-1a induces the activation of the antioxidant defenses (60). Consistently, the ablation of PGC-1a blunts some of the effects induced by exercise training in the skeletal muscle (11), and reduces the levels of different antioxidant enzymes (54). The other way round, PGC-1a overexpression in the tibialis anterior muscle decreases oxidative stress while increasing the antioxidant defenses in a model of immobilization-induced muscle atrophy (62).…”

“…6). Using such an approach, different classes of drugs have been proven effective in reverting cancer-induced muscle wasting by mimicking some of the beneficial effects induced by exercise (11). Notably, trimetazidine (TMZ) increases muscle cross-sectional area and strength in C26-bearing mice, coupled with increased oxidative metabolism and mitochondrial mass (78).…”

Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia

“…The improvement of mitochondrial function is the main mechanism underlying the effectiveness of endurance exercise in counteracting the loss of muscle mass and function in cancer cachexia, and the above-mentioned mitochondria-targeting approaches can be considered as exercise mimetics [ 32 ]. Considering that exercise feasibility in oncology patients is limited, because of several issues related to the cancer itself or to other comorbidities, rendering the patient not eligible or even exercise intolerant [ 33 ], SS-31, mimicking some of the beneficial effects of exercise, could widen the target audience for exercise-based interventions by both promoting exercise tolerance and improving the effectiveness of physical activity, as previously reported in sarcopenic aged mice [ 15 ].…”

Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target

“…Thus, an increase in muscle mass was reported in Pin et al [ 236 ], whilst cancer cachexia was not counteracted in Wang et al [ 237 ] in PGC-1α overexpressing muscles LLC-bearing mice. Both studies reported an increase in tumor mass [ 236 , 237 ], highlighting the cross-talk between muscle and tumor and revealing a possible limitation of increasing the expression of PGC-1α in muscle in cancer cachexia [ 238 ]. In addition to improving mitochondrial oxidative capacity, exercise modulates muscle metabolism by enhancing GLUT-4 translocation at the sarcolemma [ 239 ], thereby increasing the productivity of the glycolytic pathway and counteracting insulin resistance [ 239 , 240 , 241 ].…”