Reactive Oxygen Species as Agents of Fatigue

For more than three decades, muscle biologists have been fascinated by reactive oxygen species (ROS) generated in exercising muscle and the potential role that ROS may play in fatigue.

Reports in the peer-reviewed literature were analyzed and published findings integrated to synthesize an overview of ROS as agents of fatigue.

Muscle tissue contains multiple sources of ROS, and specific ROS molecules have been detected in muscle, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. These species are present throughout the tissue, i.e., myofiber organelles and cytosol, extracellular space, and intravascular compartment, and ROS concentrations increase during strenuous contractions. Direct ROS exposure evokes many of the same changes that occur in muscle during fatigue, suggesting a possible relationship. The hypothesis that ROS play a causal role in fatigue has been tested extensively, a large body of data have been compiled, and the once-controversial verdict is now in: ROS accumulation in working muscle clearly contributes to the loss of function that occurs in fatigue. This is evident in a range of experimental settings ranging from muscle fiber bundles in vitro to neuromuscular preparations in situ, from volitional exercise of small muscle groups to whole-body exercise by elite athletes.

The robust capacity of antioxidant pretreatment to delay fatigue provides compelling evidence that ROS play a causal role in this process. There are caveats to this story of course, issues related to the type of antioxidant and mode of administration. Also, the translation of this laboratory concept into clinical practice has been slow. Still, antioxidant therapy has the potential to benefit individuals who experience premature fatigue and this remains a promising area for future research.