Pathophysiological mechanisms of reduced physical activity: Insights from the human step reduction model and animal analogues

Physical inactivity represents a heavy burden for modern societies and is spreading worldwide, it is a recognised pandemic and is the fourth cause of global mortality. Not surprisingly, there is an increasing interest in longitudinal studies on the impact of reduced physical activity on different physiological systems. This narrative review focuses on the pathophysiological mechanisms of step reduction (SR), an experimental paradigm that involves a sudden decrease in participants' habitual daily steps to a lower level, mimicking the effects of a sedentary lifestyle. Analogous animal models of reduced physical activity, namely, the "wheel-lock" and the "cage reduction" models, which can provide the foundation for human studies, are also discussed. The empirical evidence obtained thus far shows that even brief periods of reduced physical activity can lead to substantial alterations in skeletal muscle health and metabolic function. In particular, decrements in lean/muscle mass, muscle function, muscle protein synthesis, cardiorespiratory fitness, endothelial function and insulin sensitivity, together with an increased fat mass and inflammation, have been observed. Exercise interventions seem particularly effective for counteracting these pathophysiological alterations induced by periods of reduced physical activity. A direct comparison of SR with other human models of unloading, such as bed rest and lower limb suspension/immobilisation, is presented. In addition, we propose a conceptual framework aiming to unravel the mechanisms of muscle atrophy and insulin resistance in the specific context of reduced ambulatory activity. Finally, methodological considerations, knowledge gaps and future directions for both animal and human models are also discussed in the review.