Muscle fatigue (MF) declines the capacity of muscles to complete a task over time at a constant load. MF is usually short-lasting, reversible, and is experienced as a feeling of tiredness or lack of energy. The leading causes of short-lasting fatigue are related to overtraining, undertraining/deconditioning, or physical injury. Conversely, MF can be persistent and more serious when associated with pathological states or following chronic exposure to certain medication or toxic composites. In conjunction with chronic fatigue, the muscle feels floppy, and the force generated by muscles is always low, causing the individual to feel frail constantly. The leading cause underpinning the development of chronic fatigue is related to muscle wasting mediated by aging, immobilization, insulin resistance (through high-fat dietary intake or pharmacologically mediated Peroxisome Proliferator-Activated Receptor (PPAR) agonism), diseases associated with systemic inflammation (arthritis, sepsis, infections, trauma, cardiovascular and respiratory disorders (heart failure, chronic obstructive pulmonary disease (COPD))), chronic kidney failure, muscle dystrophies, muscle myopathies, multiple sclerosis, and, more recently, coronavirus disease 2019 (COVID-19). The primary outcome of displaying chronic muscle fatigue is a poor quality of life.
The main underlying factor behind the loss of muscle mass, malnutrition, and negative nitrogen balance is an increase in skeletal muscle protein degradation. This occurs on a background of inflammatory responses to trauma or infection, increased circulating cytokine, glucagon, epinephrine, and glucocorticoid treatment, hyperglycemia-mediated secondary infections, and induction of muscle insulin resistance. The immobilization is also an important factor triggering the preferential myosin loss, atrophy, and loss of specific force in fast- and slow-twitch muscle fibers with the loss of strength, especially in the quadriceps and extensors [6]. The critical implications of muscle protein loss extend to poor clinical outcomes such as wound healing, decreased ambulation, and increased risk of thromboembolic complications. There is also evidence that trauma and sepsis can lead to pulmonary complications due to a catabolic response in the respiratory muscles [7], extending to peripheral skeletal muscles [8].
Although the amount of protein that is degraded in healthy subjects of a given age equals typically the amount of protein synthesized, the whole-body protein turnover (protein synthesis + protein degradation) decreases gradually with ageing after peaking through puberty.
A classic example of a disease associated with chronic muscle fatigue is multiple sclerosis. Here, the suppressor function of regulatory T cells (Tregs), which have a role in regulating or suppressing other cells of the immune system, thereby controlling the immune response to self and foreign particles (antigens), is impaired for vague reasons. We recently provided evidence that supports a novel mechanism underlying diminished Treg function in multiple sclerosis. Thus, infections that activate the toll-like receptor 2 (TLR2) in vivo (specifically through TLR1/2 heterodimers) could shift the ratio between the Treg and the HIV inhibitor T helper 17 (Th17) cells’ balance toward a pro-inflammatory state in multiple sclerosis, thereby promoting disease activity and progression [48].
COVID-19 is a recent viral infection that has spread worldwide and has been identified to affect multiple organ systems, including the nervous system. There is now a mounting body of evidence to suggest the existence of a long-term, post-Covid muscle fatigue syndrome even after mild cases of viral infections. There is, so far, no evident description of the underlying pathology. Muscle deconditioning, immune- or virus-mediated neuropathy, and exercise hyperventilation have been hypothesized to play an essential role in developing debilitating symptoms [49]. Nevertheless, due to the presence of robust and durable systemic inflammatory responses to the viral load (such as the formation of ROS and NO by immune cells during chronic inflammation) in conjunction with a lengthy bed immobilization and medication initially intended to dampen the immune responses, which otherwise also stimulates muscle atrophy (e.g., the steroid dexamethasone), it may not be, therefore, surprising that these factors could contribute to accelerating the energy-independent proteolytic activation of protein degradation via calcium (calpains) and TNF-α (E3-ligases) along with the dexamethasone-induced upregulation of myostatin [50]. Collectively, these outcomes might explain the initiation of muscle atrophy and muscle fatigue.
This entry is adapted from the peer-reviewed paper 10.3390/ijms222111587