Marco V. Narici

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.

Background Efforts to enhance diagnostic measures for sarcopenia have led to an increased focus on the screening utility of blood‐based biomarkers. In this regard, circulating neurofilament light chain (NfL) levels are a potent indicator of axonal damage and have been linked with several neurological disorders. However, despite the strong neurogenic contribution to skeletal muscle health, no studies have explored the relevance of NfL concentrations to sarcopenia. With that in mind, this study aimed to examine the association between plasma NfL concentration and sarcopenic domains. Methods Three hundred adults aged between 50 and 83 years participated to this study (male participants, n = 150; mean age: 64.2 ± 8.7 years and female participants, n = 150; mean age: 63.9 ± 8.3 years). Body composition was assessed using dual‐energy X‐ray absorptiometry, and a skeletal muscle index (SMI) was calculated. Muscle strength was assessed with hand dynamometry. Sarcopenia was classified using the European Working Group on Sarcopenia in Older People criteria. Plasma NfL concentration was determined using a highly sensitive, enzyme‐linked immunosorbent assay. Results Neurofilament light chain levels were associated with grip strength and SMI ( P = 0.005 and P = 0.045, respectively) and were significantly elevated in sarcopenic individuals, compared with non‐sarcopenic participants ( P < 0.001). Individuals with pre‐sarcopenia (either low grip strength or low SMI) had significantly higher NfL levels, compared with healthy controls ( P = 0.001 and P = 0.006, respectively). Male participants with either low grip strength or low SMI had significantly raised NfL levels ( P = 0.006 and P = 0.002, respectively), while in female participants, NfL concentrations were significantly elevated only in those with low grip strength ( P = 0.049). NfL concentration displayed acceptable diagnostic accuracy for sarcopenia (area under the curve = 0.726, P < 0.001). Conclusions Our study clearly demonstrates the indicative pertinence of circulating NfL levels to sarcopenic domains, supporting its potential use as a biomarker of sarcopenia. More studies are needed, however, to further illuminate the diagnostic value of circulating NfL. Future research should explore whether NfL levels are more powerfully linked with muscle strength than mass and whether sex mediates the relevance of NfL concentrations to sarcopenic phenotypes.