The Impact of Exercise Capacity on Complex Neuromuscular Adaptations: A Narrative Review Based on a Rat Model System Selectively Bred for Low and High Response to Training.

There is scientific evidence that supports the association between aerobic exercise capacity and the risk of developing complex metabolic diseases. The factors that determine aerobic capacity can be categorized into two groups: intrinsic and extrinsic components. While exercise capacity is influenced by both the intrinsic fitness levels of an organism and the extrinsic factors that emerge during training, physiological adaptations to exercise training can differ significantly among individuals. The interplay between intrinsic and acquired exercise capacities represents an obstacle to recognizing the exact mechanisms connecting aerobic exercise capacity and human health. Despite robust clinical associations between disease and a sedentary state or condition, the precise causative links between aerobic exercise capacity and disease susceptibility are yet to be fully uncovered. To provide clues into the intricacies of poor aerobic metabolism in an exercise-resistant phenotype, over two decades ago a novel rat model system was developed through two-way artificial selection and raised the question of whether large genetic differences in training responsiveness would bring about aberrant systemic disorders and closely regulate the risk factors in health and diseases. Genetically heterogeneous outbred (N/NIH) rats were used as a founder population to develop contrasting animal models of high versus low intrinsic running capacity (HCR vs. LCR) and high versus low responsiveness to endurance training (HRT vs. LRT). The underlying hypothesis was that variation in capacity for energy transfer is the central mechanistic determinant of the divide between complex disease and health. The use of the outbred, genetically heterogeneous rat models for exercise capacity aims to capture the genetic complexity of complex diseases and mimic the diversity of exercise traits among humans. Accumulating evidence indicates that epigenetic markers may facilitate the transmission of effects from exercise and diet to subsequent generations, implying that both exercise and diet have transgenerational effects on health and fitness. The process of selective breeding based on the acquired change in maximal running distance achieved during a treadmill-running tests before and after 8 weeks of training generated rat models of high response to training (HRT) and low response to training (LRT). In an untrained state, both LRT and HRT rats exhibit comparable levels of exercise capacity and show no major differences in cardiorespiratory fitness (maximal oxygen consumption, VO_2max). However, after training, the HRT rats demonstrate significant improvements in running distance, VO_2max, as well as other classic markers of cardiorespiratory fitness. The LRT rats, on the other hand, show no gain in running distance or VO_2max upon completing the same training regime. The purpose of this article is to provide an overview of studies using LRT and HRT models with a focus on differences in neuromuscular adaptations. This review also summarizes the involved molecular and cellular signaling pathways underlying skeletal muscle adaptations in LRT models in comparison to the HRT model, which responds positively to endurance training. The LRT-related adverse effects in neuromuscular responses seem to be primarily driven by: (i) impaired glucose tolerance or impaired insulin sensitivity, (ii) increased extracellular matrix (ECM) remodeling, (iii) loss of type I muscle fibers, (iv) mitochondrial dysfunction, and (v) intricate cellular signaling orchestrated by TGF-ß1-JNK and TNF-α-MAPK pathways. Alternatively, the HRT model demonstrates improved neurovascular and muscle remodeling responses and increased central nervous system excitability, which might reflect an inherent protective mechanism to stress events.