Adattamenti Metabolici e Strutturali del Muscolo Scheletrico in Risposta a un Breve Periodo di Inattività Fisica mediante il Modello di Step Reduction

Physical inactivity, defined as decreased or absent physical activity, is a growing global health challenge that impacts quality of life and is associated with substantial risk of developing chronic diseases, negatively affecting overall health and longevity. With contemporary lifestyle changes, particularly following the COVID-19 pandemic and the rapid development of technology, prolonged reductions in daily physical activity have become an almost unavoidable aspect of modern life. Skeletal muscle is one of the most dynamic and plastic tissues in the body, capable of altering its structure, metabolism, and function in response to external stimuli. It also acts as a key regulatory organ influencing the homeostasis of multiple other tissues and organs. Therefore, maintaining skeletal muscle homeostasis is crucial for overall body health. While the effects of severe muscle disuse have been extensively investigated, the impact of milder reductions in physical activity is less documented. In this context, the step reduction (SR) model represents a valuable model that closely mimics the sedentary lifestyle characteristic of modern societies. To clarify the impact of a sedentary lifestyle on metabolic and skeletal muscle adaptations, this study employed the SR model. Thirty-three healthy young adults (16 males, 17 females) underwent a 14-day period of SR, during which daily ambulatory steps were reduced from approximately 9,000 to < 1,500 steps/day. The experimental design involved pre- and post-intervention assessments, including an incremental cycling test to determine maximal oxygen consumption (VO2max), near-infrared spectroscopy (NIRS) to evaluate muscle oxygen uptake recovery kinetics, and vastus lateralis muscle biopsies analyzed by histology, immunofluorescence, and SDS-PAGE to assess fiber type size, distribution, and capillarization. Western blotting and High-Resolution Respirometry (HRR) were used to evaluate mitochondrial content, dynamics, and intrinsic mitochondrial function. Following 14 days of SR, VO2max remarkably decreased, indicating that the ability to transport and utilize oxygen is compromised very quickly. Furthermore, in vivo NIRS determination showed a decline in oxygen utilization kinetics (mVO2max decline) at the skeletal muscle level, suggesting that the performance decline is not only central but also involves a reduced efficiency of the skeletal muscle in extracting and utilizing oxygen. Interestingly, this deficit does not result from structural or functional mitochondrial damage. Markers of mitochondrial content (citrate synthase, TOM20), biogenesis (PGC-1α), and dynamics (MNF1, MNF2, 5 OPA1, DRP1, FIS1), as well as intrinsic mitochondrial respiration, were not negatively affected by SR. Moreover, analyses of muscle capillarization (capillary density, C:F ratio, capillary domain area) showed no significant changes in response to SR, suggesting that the architecture of microvascular support is not responsible for the metabolic muscle deficit (i.e., mVO2max decline). Regarding muscle structure, analysis of cross-sectional area (CSA) showed an absence of muscle atrophy. However, a shift from slow-twitch towards fast-twitch fibers was found in response to SR, as evidenced by Myosin Heavy Chain (MHC) isoform content and distribution. This indicates that adaptations in muscle phenotype precede muscle mass loss. Overall, these data suggest that short-term SR induces early systemic and metabolic deterioration. Skeletal muscle, while maintaining its mitochondria and vascular support intact,shows signs of functional and phenotypic maladaptation even before tissue loss occurs. Such rapid deterioration underscores the critical importance of maintaining daily movement to counteract the early onset of metabolic and cardiovascular dysfunction.