Reactive oxygen species in the pathogenesis of sarcopenia

Abstract

One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.

Keywords: Aging; Mitochondria; Neuromuscular junction; Sarcopenia; Skeletal muscle.

Fig. 1.. Summary of tissue specific antioxidant models.

The table above illustrates the genetic mouse models used to investigate the impact of neuronal versus muscle oxidative stress on muscle atrophy and weakness. Deleting key antioxidant enzymes specifically in skeletal muscle results in muscle weakness and degeneration of the NMJ. Similarly, when these enzymes are deleted in neurons, we observe muscle atrophy, weakness, and NMJ degeneration. These findings suggest that the sarcopenia phenotype is triggered by peroxides originating from both muscle and motor neurons. Created in BioRender. Van Remmen, H. (2024) https://BioRender.com/n40q480.

Fig. 2.. Impact of hydroperoxides on sarcopenia.

Schematic showing that aging increases mitochondrial hydroperoxide generation. Studies from our laboratory and others have shown that mitochondrial hydroperoxide generation can lead to NMJ degeneration and denervation. Denervation often occurs before other hallmarks of sarcopenia such as muscle loss and dysfunction. Studies from our laboratory show that mitochondrial lipid hydroperoxide generation is elevated in denervated muscle, which leads to increased muscle protein breakdown. In addition, electron transport chain ROS is also associated with increased muscle protein breakdown. These data from multiple laboratories suggest that hydroperoxides may be a causal agent of sarcopenia.

Fig. 3.. Impact of oxidative stress on muscle contractile function.

Skeletal muscle produces force through excitation-contraction coupling (E-C coupling), which involves the membrane excitability and sensing of an action potential of the sarcolemma, and the release and regulation of Ca²⁺ ions from and back to sarcoplasmic reticulum (SR), and finally the relative interactions between contractile filaments to output force production. With elevated oxidative stress, deleterious oxidative modifications can occur on one or multiple sites within the E-C coupling system, which might lead to the impaired muscle force generation.