Interaction of Sepsis, Disuse, and Aging on Skeletal Muscle Function and Remodeling in Male and Female Mice

Sepsis is associated with skeletal muscle weakness and atrophy, particularly in older and immobilized patients; however, how sepsis interacts with disuse, reloading, aging, and biological sex remains poorly defined.

Young (5 mo) and older (20 mo) male and female C57BL/6J mice underwent cecal ligation and puncture (CLP) or sham surgery followed by hindlimb suspension (HLS) or normal ambulation (NA) for 7 days (Experiment 1). A separate cohort underwent 3 days of reloading after HLS (REL; Experiment 2). Outcomes included survival, body mass, soleus force-frequency, myofiber cross-sectional area (CSA), macrophage infiltration (CD68⁺), extracellular matrix (ECM), and satellite cells (Pax7⁺).

Survival was preserved in septic young mice (> 84%) but reduced in older septic mice (~51%-60% males; ~57% females). Disuse was the primary driver of body mass loss during HLS/REL, with older females exhibiting the greatest decline (day 11: -19.8% ± 6.8% Sham; -17.4% ± 6.5% CLP). Disuse reduced median fiber CSA by ~27%-46% across cohorts (e.g., young males: 1840 ± 189 to 997 ± 345 μm²). In Experiment 1, CD68⁺ macrophages increased most with combined sepsis and disuse, whereas ECM expansion was observed only in males. Pax7⁺ satellite cells were markedly reduced in young males with sepsis and disuse and in older mice of both sexes with sepsis. Following REL, older septic males retained force deficits, and septic females remained significantly atrophic.

Muscle disuse amplifies sepsis-induced myopathy in an age- and sex-dependent manner, with incomplete early recovery after reloading.