Delayed muscle recovery post disuse in older septic mice

Background: Sepsis, a life-threatening overreactive response of the immune system to an infection, is predominant in the older population (>65 years of age). Advances in intensive care therapies have improved survival rates, resulting in an increased number of septic survivors. Septic patients experience prolonged periods of bed rest, resulting in disuse of functional skeletal muscle. Approximately 75% of septic survivors develop sepsis-induced myopathy, characterized by muscle weakness and atrophy. How septic skeletal muscles respond to weight bearing after a period of bed rest remains unknown. To address this concern, we employed a clinically relevant model that combines a septic insult with hindlimb disuse followed by re-ambulation in older male and female mice. We hypothesized that sepsis combined with disuse would result in exacerbated muscle weakness and atrophy during re-ambulation. Methods: Male and female C57BL/6 mice (78 weeks old), provided by the National Institutes on Aging (NIA), underwent cecal ligation and puncture (CLP) or sham surgeries. Animals were randomly assigned to the following groups: Sham Hindlimb Suspension (HLS) (Male Sham HLS, N=8; Female Sham HLS, N=9) and CLP HLS (Male CLP HLS, N=8; Female CLP HLS, N=9). Four days post-surgery, animals were subjected to HLS for 7 days. Animals were reloaded on day 7 and remained under normal ambulation for 3 days at which point terminal experiments were performed. Hindlimb muscles were dissected and mounted for histological assessments of muscle cross-sectional area (CSA). Additionally, ex vivo assessments of soleus contractile force were performed. Results: The survival rate was 57.1% among male and 56.3% among female animals undergoing CLP HLS. The survival rate was 100% among Sham animals in both sexes. We found a major effect of sepsis driving a decrease in peak of absolute force (Sham HLS: 218.6 ± 7.6 vs. CLP HLS: 191.3 ± 7.4 mN; p = 0.02) and specific force (Sham HLS: 20.2 ± 0.6 vs. CLP HLS: 16.9 ± 0.7 N/cm 2 ; p < 0.001) in males. Interestingly, no differences in force were found between CLP HLS and Sham HLS among females (p > 0.05). Histological analysis demonstrated that disuse-induced atrophy was not resolved 72 hours after hindlimb reloading in both male and female animals. Conclusion: Our findings indicate that aged septic male mice undergoing reloading after HLS exhibit exacerbated weakness compared to Sham animals. Additionally, female mice demonstrate a resilient response to sepsis-induced weakness. This study was supported by National Institutes of Health (NIH) R21 AG072011 to OL. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.