Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training

Abstract

Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Transmission of external stimuli to intracellular effector proteins via signalling pathways is a highly regulated and controlled process that determines muscle mass by balancing protein synthesis and protein degradation. An impaired balance between protein synthesis and breakdown leads to the development of specific myopathies. Sarcopenia and cachexia represent two distinct muscle wasting diseases characterized by inflammation and oxidative stress, where specific regulating molecules associated with wasting are either activated (e.g. members of the ubiquitin-proteasome system and myostatin) or repressed (e.g. insulin-like growth factor 1 and PGC-1α). At present, no therapeutic interventions are established to successfully treat muscle wasting in sarcopenia and cachexia. Exercise training, however, represents an intervention that can attenuate or even reverse the process of muscle wasting, by exerting anti-inflammatory and anti-oxidative effects that are able to attenuate signalling pathways associated with protein degradation and activate molecules associated with protein synthesis. This review will therefore discuss the molecular mechanisms associated with the pathology of muscle wasting in both sarcopenia and cachexia, as well as highlighting the intracellular effects of exercise training in attenuating the debilitating loss of muscle mass in these specific conditions.

Keywords: Cachexia; Exercise training; Molecular analysis; Muscle wasting; Sarcopenia.

Figure 1

The effects of exercise on the signalling pathways associated with muscle growth and wasting in sarcopenia and cachexia. Muscle wasting is commonly induced by elevated inflammation and reactive oxygen species (ROS), which increase signalling of protein degradation via a number of key pathways—a key one mediated by the FoxO transcription factors, which activate the ubiquitin-proteasome system (UPS) and autophagy. In addition, sarcopenia and cachexia are also associated with lower levels of the insulin-like growth factor 1 (IGF-1), which impairs protein synthesis by suppressing the PI3K-Akt-mTOR pathway. This pathway can also be repressed by myostatin, which binds to its receptor activin A receptor type B (ActRIIB) to further stimulate atrogene transcription via SMAD2 or SMAD3. Exercise, however, stimulates a number of pathways that can increase protein synthesis whilst reducing degradation (as denoted by dashed lines), which attenuates muscle wasting and, in some circumstances, can lead to muscle growth. Exercise can exert potent anti-inflammatory and anti-oxidative effects and also reduce myostatin signalling, which collectively represses the transcription of atrogenes and consequent protein degradation. Simultaneously, exercise also increases IGF-1 levels to induce protein synthesis, with the subsequent activation of mTOR concomitantly suppressing FoxO signalling. An important exercise-induced transcription factor is PGC-1α, and also its isoform PGC-1α4, with the former down-regulating proteolysis and the latter increasing synthesis via the IGF-1 pathway.