Sarcouncil Journal of Medical Series

Abstract: Mitochondrial dysfunction in skeletal muscle underlies the pathophysiology associated with classic hallmarks of aging, metabolic disease, neuromuscular disorders, and physical inactivity. While voluntary exercise remains the single most effective physiological intervention for improving mitochondrial content, efficiency, and adaptability, many patient cohorts are not capable of executing adequate physical activity to produce such adaptations. As such, neuromuscular electrical stimulation (NMES) has appeared on the horizon as a promising exercise mimetic capable of stimulating skeletal muscle under the loss of volitional control. The purpose of this narrative review is to integrate findings from human research and hypothesis-driven basic science investigation to develop a comprehensive framework explaining how NMES affects skeletal muscle mitochondrial function. The thesis of this manuscript is that NMES induces mitochondrial adaptation through two non-mutually exclusive processes. Firstly, muscle contractions stimulated by electric impulses are sufficient to induce metabolic stress to activate canonical muscle signaling pathways, especially those mediated by AMPK and PGC-1α. Secondly, there is nascent evidence to suggest that NMES may stimulate muscle contraction-induced secretion of myokines, which may initiate systemic endocrine signals to modulate mitochondrial function. With this dual mechanism in mind, NMES could move beyond a purely passive approach for atrophy prevention and take on an active role in stimulating metabolism in a way that recreates the essential molecular elements of exercise. Finally, the potential implications of this paradigm for exercise-capacity-limited populations such as those with spinal cord injury, metabolic disease, cancer-associated sarcopenia, or critical illness will be explored in the final section.