Sex-Specific Differences in Septic Outcome: Does Mitochondrial Function Play A Role?

Objectives: Systemic inflammatory response after surgery and sepsis share many common mechanisms, and many comorbidities contribute to its course. We assessed the effect of female sex during polymicrobial sepsis and quantified cardiac and mitochondrial function.

Methods: In male and female mice, sepsis was induced by intraperitoneal injection of human feces. 24-hour survival was documented and sepsis severity (clinical severity score), cardiac and mitochondrial function were assessed after 6 and 24 hours. Mice without sepsis served as control. Mitochondrial function was measured in isolated mitochondria.

Result: Sepsis induction resulted in severe microbial sepsis within the first 24 hours in both, male and female. Unexpectedly, 24-hour survival was greater in male mice. After 24 hours, approximately 50% of male and 25% of female mice were alive. Clinical severity score (CSS) was equally elevated after 6 hours but more increased in male after 24 hours (basal: 6 vs. 24 hours: f: 4.0 ± 0.0 vs. 6.9 ± 0.4 vs. 6.0 ± 0.7; m: 4.0 ± 0.0 vs. 7.1 ± 0.3 vs. 8.3 ± 0.7). Plasma levels of proinflammatory (IL6, TNFα) and anti-inflammatory (IL-10) cytokines were highly elevated 6 hours after septic insult decreasing to normal values at 24 hours.

Sepsis led to a temporary restriction of cardiac function in male and female mice. Heart rate was increased in septic mice after 6 hours and normalized after 24 hours. Cardiac output was significantly decreased only in male mice after 6 hours, but normalized after 24 hours. Diastolic function was significantly impaired after 6 hours but normalized after 24 hours in both, male and female (E/E′: f: 25.9 ± 0.9 vs. 21.1 ± 1.3 vs. 24.1 ± 1.6; m: 28.7 ± 0.9 vs. 21.4 ± 1.3 vs. 25.3 ± 1.4). In contrast, systolic function was not affected.

Mitochondrial respiratory capacity (state 3 respiration) significantly decreased in male mice after 24 hours with complex I and II substrates (palmitoylcarnitine + malate: m 81.9 ± 3.6 vs. 80.4 ± 14.6 vs. 53.3 ± 1.3 natomsO/min/CS). However, mitochondrial function in female mice was unaffected in sepsis (f: 58.0 ± 7.4 vs. 58.8 ± 3.2 vs. 60.1 ± 4.8 natomsO/min/CS).

Conclusion: Our results suggest that sepsis in males is better tolerated than sepsis in females. However, the differences between male and female mice cannot be explained through mitochondrial function.

Publication History

Article published online:
19 February 2021