Sepsis, Disuse, Aging, and Sex: A Toxic Quartet Crippling Muscle Recovery

Sepsis survivors face profound muscle weakness, which is often exacerbated by immobility in the intensive care unit (ICU), advanced age, and sex disparities; however preclinical models have historically overlooked these interacting factors. A recent landmark study in Acta Physiologica by Muller and colleagues [1] integrates cecal ligation and puncture (CLP)-induced sepsis with hindlimb suspension (HLS) in young (5 months) and older (20 months) male and female C57BL/6J mice, thereby recapitulating bedrest in septic patients and incorporating reloading to probe early recovery dynamics. Disuse emerges as the dominant driver of catastrophic atrophy (27%–46% reduction in median soleus fiber cross-sectional area, CSA) and absolute force deficits across all groups. In contrast, sepsis alone subtly impairs intrinsic contractile quality (specific force) most strikingly in females. Survival plummets to ~50%–60% in older septic mice versus > 84% in young mice, while disuse exerts a negligible impact on mortality, spotlighting age as the primary vulnerability in sepsis. Each year, sepsis affects nearly 50 million patients globally, many of whom experience muscle weakness that persists for months after hospital discharge, driving up readmissions and reducing quality of life [2]. In this study, HLS mirrors the prolonged immobility common in septic shock, identifying disuse (rather than sepsis alone) as the main culprit for the dramatic muscle wasting and force loss. Body mass declines by 10%–21%, with the greatest losses observed in older females. Brief reloading after disuse fails to fully restore function: older males retain high-frequency force deficits, while females exhibit persistent fiber atrophy. These findings echo clinical trials of early mobilization, which demonstrate benefit in some patients, but reduced efficacy in the elderly or septic, signaling the need for tailored rehabilitation strategies [3]. Across all ages and conditions, disuse slashes absolute muscle force by 25%–50% at physiological stimulation frequencies, accompanied by similar reductions in fiber sizes (young males lose nearly half their CSA). When force is normalized to fiber size (specific force), however, a marked sex difference is revealed: females exhibit greater intrinsic contractile impairment, suggesting disruptions in calcium handling or myofilament interactions specific to their muscle physiology. In males, by contrast, weakness is more closely linked to loss of muscle mass. Clinically, these findings suggest that women may benefit from therapies that preserve muscle quality (such as agents that stabilize contraction machinery), while men may respond more to antiatrophy measures. The synergy of sepsis and disuse increases macrophage infiltration up to eightfold, peaking in young females, and promotes collagen accumulation in the male muscle extracellular matrix—findings that mirror human intensive care biopsies. Muscle stem cells, which are essential for repair, decline dramatically from dozens to only a few per section in affected young males and older septic mice. Following reloading, inflammation persists in males and young females, while stem cell numbers stabilize in the young but not aged males. Together, these microenvironmental alterations help explain the long-term recovery deficits in sepsis survivors, extending beyond simple protein breakdown to chronic inflammatory and regenerative barriers. Imagine bedside ultrasound measurement of fiber size or stiffness as a clinical proxy for these experimental findings, particularly as low specific force already predicts readmission risk [4, 5]. Early neuromuscular stimulation may attenuate disuse atrophy by 20%, as suggested by pilot trials, while anti-inflammatory drugs like tocilizumab (proven in sepsis trials) could mitigate macrophage-driven inflammation [6]. In aged patients with depleted stem cells, senolytics or Notch pathway activators show promise in preclinical regeneration models [6]. This study's survival rates align with real-world data in elderly sepsis populations, supporting the development of stratified rehabilitation protocols: such as high-intensity training for young males and endurance-focused exercise for older females. Sepsis-induced muscle weakness imposes substantial economic and clinical burdens, yet current guidelines largely overlook age and sex interactions. This recent study in Acta Physiologica calls for trials that report outcomes by sex, incorporate serial muscle imaging in survivors, and implement rehabilitation strategies tiered by vulnerability (early for all, intensified for the old and female) (Figure 1). By dissecting how disuse amplifies sepsis in living muscle, this study bridges mechanistic rodent research to human bedside care, embodying Acta Physiologica's mission to illuminate mechanisms driving clinical breakthroughs. Every fiber recovered could rewrite survivor fates. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.