Intramuscular pathways of maladaptation in overtraining syndrome

Planned and progressive exercise, that is, exercise training, is essential for promoting skeletal muscle adaptation and improvements in athletic performance. However when the training demands exceed the ability to recover, it may lead to a state of persistent maladaptation. A prolonged imbalance between training or competition and recovery can cause extended periods of performance impairment, known as functional or non-functional overreaching, which may progress to overtraining syndrome (OTS). This condition can significantly impair athletic development and, in severe cases, cause athletes to retire earlier than expected. Skeletal muscle is key for physical performance, including the ability to move and utilise energy. Impaired physical performance is a hallmark of OTS, reflecting the central role of skeletal muscle dysfunction in its development and progression. In this review we discuss the potential mechanisms contributing to skeletal muscle impairments in OTS. These include central and peripheral neural fatigue, endocrine dysregulation and altered hormonal responses, impaired mitochondrial bioenergetics and oxidative stress and systemic inflammation. We also draw parallels between maladaptive response in overreaching and OTS and those typically observed in chronic inflammatory and catabolic conditions, as these may offer insights into underlying mechanistic understanding of OTS, as well as future treatment strategies. Because replicating the full clinical picture of OTS in humans in experimental settings is constrained by practical challenges, we further discuss animal models that may allow for controlled investigations of external variables and thus enable enhanced understanding of its complex pathophysiology.