Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target

Abstract

Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions.

Keywords: diet; epigenetics; muscle wasting; physical exercise; skeletal muscle metabolism.

Figure 1

Metabolic reprogramming of skeletal muscle during aging and non-pharmacological approaches to counteract sarcopenia. Skeletal muscle metabolic remodeling during aging is associated with a reduction in the number of glycolytic fibers, reduced mitochondrial synthesis, and increased catabolism (red box). Decreased anaerobic glycolysis and impaired mitochondrial activity result in elevated protein catabolism and loss of muscle maintenance. Sarcopenic muscle shows reduced muscle fiber size (atrophy) and number (hypoplasia), and is accompanied by fat infiltration and connective tissue deposition. Among the main non-pharmacological approaches for the prevention of muscle mass loss during aging are long-term caloric restriction, dietary supplementation, and aerobic exercise (green box).

Figure 2

Skeletal muscle metabolic reprogramming and proposed approaches to counteract disease progression. Among the metabolic pathways affected in ALS muscle are glucose and lipid metabolism, reactive oxygen species (ROS) production and insulin signaling (red box). Reduced glucose transport and uptake, increased lipid metabolism, and ROS-mediated oxidative stress result in metabolic dysfunction. A high-fat-low-carb diet and physical exercise have been shown to have protective effects on neurons and skeletal muscles in ALS.

Figure 3

Metabolic reprogramming in cancer-induced cachexia and beneficial effects of exercise. In the red box are summarized the multiple pro-cachectic effects mediated by cancer. Impaired autophagy, energy expenditure, and denervation result in unbalanced protein homeostasis, overall leading to muscle wasting. In the green box are listed the anti-cachectic protective effects induced by exercise. Increased anti-inflammatory cytokines and suppression of the catabolic pathways lead to increased muscle mass and improved metabolism.