Endurance exercise protects skeletal muscle against both doxorubicin-induced and inactivity-induced muscle wasting

Abstract

Repeated bouts of endurance exercise promotes numerous biochemical adaptations in skeletal muscle fibers resulting in a muscle phenotype that is protected against a variety of homeostatic challenges; these exercise-induced changes in muscle phenotype are often referred to as "exercise preconditioning". Importantly, exercise preconditioning provides protection against several threats to skeletal muscle health including cancer chemotherapy (e.g., doxorubicin) and prolonged muscle inactivity. This review summarizes our current understanding of the mechanisms responsible for exercise-induced protection of skeletal muscle fibers against both doxorubicin-induced muscle wasting and a unique form of inactivity-induced muscle atrophy (i.e., ventilator-induced diaphragm atrophy). Specifically, the first section of this article will highlight the potential mechanisms responsible for exercise-induced protection of skeletal muscle fibers against doxorubicin-induced fiber atrophy. The second segment will discuss the biochemical changes that are responsible for endurance exercise-mediated protection of diaphragm muscle against ventilator-induced diaphragm wasting. In each section we highlight gaps in our knowledge in hopes of stimulating future research in this evolving field of investigation.

Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways

“…Except for pharmacological treatments, emerging evidence suggests that exercise might ameliorate the detrimental effects of doxorubicin on skeletal muscle tissue. A recent review of Powers et al (2019), including preclinical studies, suggests that endurance exercise training performed prior to doxorubicin treatment protects against doxorubicin‐induced skeletal muscle atrophy by the prevention of excess oxidative stress and the activation of proteolytic signalling pathways . Indeed, the beneficial effects of exercise are confirmed in human studies with several clinical trials showing that combined resistance and endurance training has positive effects on muscle strength in cancer patients undergoing chemotherapy .…”

The Role of Calpains in Skeletal Muscle Remodeling with Exercise and Inactivity-induced Atrophy

“…In this regard, skeletal muscle responds to periods of muscle inactivity by initiating processes that facilitate muscle atrophy. Inactivity-induced muscle atrophy occurs as a result of conditions that significantly decrease the work performed by skeletal muscle such as limb-immobilization, prolonged bedrest, and mechanical ventilation-induced inactivity of inspiratory muscles [12,[82][83][84][85][86][87]. Unfortunately, prolonged inactivity results in skeletal muscle atrophy that is detrimental due to a reduced forcegenerating capacity of skeletal muscle.…”

Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy

“…Atrogin1 and MuRF1 increased during muscle atrophy, and, as such, it is verified with the use of DOX [ 12 ]. On the other hand, endurance and resistance exercise protects against the disorders in the skeletal muscle resulted from the use of doxorubicin therapy [ 11 , 13 , 26 ]. In this study, we demonstrated that DOX upregulates the expression of these proteins and that EXER performed during and after chemotherapy minimizes muscle atrophy caused by this pharmacological treatment.…”

“…Physical activity is associated with a lower prevalence of various types of cancer, including colon, endometrial, breast, prostate, gastroesophageal, ovarian, pancreatic and lung cancers [ 9 ]. In fact, endurance exercise (EXER) offers an approach to managing muscle atrophy and reduces tumor growth [ 10 , 11 ]. Moreover, studies have suggested that in the absence of a tumor, physical exercise is able to protect the muscle during DOX treatment [ 12 , 13 , 14 ].…”