Muscle at Risk: How Physical Inactivity and Systemic Inflammation Affect Skeletal Muscle Health

Physical inactivity causes declines in various physiological systems and contributes to metabolic diseases. Skeletal muscle mass loss due to inactivity is linked to decreased insulin sensitivity and altered glucose metabolism, causing insulin resistance. However, the specific molecular and metabolic changes underlying these inactivity-induced effects remain unclear. In Chapter 2, a human bed rest study explored body composition, insulin and glucose metabolism, and mitochondrial function. Results indicated that short-term bed rest causes intracellular glycogen and lipid accumulation (nutrient overload), while prolonged inactivity exacerbates lipid storage, linked to local and systemic inflammation and lipotoxicity, alongside reduced mitochondrial function. These findings suggest nutrient overload as a primary driver of metabolic adaptations, with insulin insensitivity potentially acting as a protective mechanism against further nutrient accumulation. Inactivity often coincides with chronic systemic inflammation, as seen in ageing, chronic disease, obesity, and post-surgery. Chapter 3 investigated the role of the NLRP3 inflammasome in inflammation-related muscle alterations. Cultured myotubes exposed to lipopolysaccharide (LPS) exhibited NLRP3 inflammasome activation, leading to mitochondrial ROS production and impaired muscle growth. Prolonged LPS exposure further damaged cells via IL-1β production, likely reducing protein synthesis. Treating cells with MCC950, an NLRP3 inhibitor, mitigated these growth impairments, indicating a promising therapeutic approach for inflammation-driven muscle wasting. Systemic inflammation and physical inactivity may have compounding effects on muscle deterioration, yet this interaction is understudied. In Chapter 4, a preclinical mouse model examined the combined effects of inactivity (hindlimb suspension) and inflammation (LPS injection). Results showed significant muscle and body mass loss, especially upon combined conditions. Muscle atrophy was shown by reduced fibre size, with an impaired anabolic response evident through reduced leucine-stimulated protein synthesis and decreased Akt phosphorylation. Combined unloading and LPS induced metabolic stress in skeletal muscle, leading to anabolic resistance, increased proteolysis, and heightened inflammation. Chapter 5 focused on muscle alterations in acute COVID-19 and post-COVID-19 (PASC) patients. Severe COVID-19 and PASC patients often face muscle weakness, exercise intolerance, and muscle atrophy, alongside metabolic changes and immune cell infiltration. Contributing factors include systemic inflammation, inactivity, hypoxemia, and malnutrition, all common in ICU-acquired weakness. Muscle alterations in PASC may stem from direct viral invasion or an abnormal immune response, showing similarities with chronic fatigue syndrome and warranting further study. In Chapter 6, a novel method for estimating vastus lateralis (VL) muscle volume was developed to assess muscle mass in critical illness myopathy associated with inactivity and inflammation. This method, using a constant “muscle shape factor” applied to VL muscle length and cross-sectional area, achieved high accuracy (5.3±3.4% relative difference, R²=0.99). Two practical approaches - ultrasound image stitching and muscle thickness measurement - proved effective and feasible for bedside use, providing a reliable, safe, and affordable tool for clinical and research settings to monitor muscle size changes over time. Overall, this thesis delivers valuable insights into how inactivity and inflammation impact skeletal muscle from molecular to whole-body levels. Inactivity-induced nutrient overload contributes to insulin insensitivity, lipotoxicity, and mitochondrial dysfunction, with insulin insensitivity possibly serving as an adaptive response to limit further metabolic stress. The NLRP3 inflammasome emerges as a key player in inflammation-driven muscle wasting, presenting a potential therapeutic target. Furthermore, the combined effect of inactivity and systemic inflammation exacerbates muscle atrophy and metabolic dysfunction, resulting in anabolic resistance and diminished mitochondrial function. The new VL muscle volume estimation method aids muscle monitoring, especially relevant for vulnerable populations such as the elderly and critically ill. These findings highlight the need for interventions to preserve muscle function and metabolic health in at-risk populations. Future research should aim at developing targeted strategies to counter muscle atrophy and enhance metabolic function in conditions of inactivity and inflammation.