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Updated: May 31, 2026
A Preclinical Model of Sepsis-Induced Myopathy with Disuse in Mice
Published on: June 14, 2024
Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat
Mani Chopra1, Honey B Golden, Srinivas Mullapudi
1Department of Biomedical Sciences, Texas A&M Health Science Center Baylor College of Dentistry, Dallas, Texas, United States of America.
Background:
We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival.
Methodology/Principal Findings:
Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.
Conclusion:
The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.
Insights
5-Hydroxydecanoic acid (5HD) reversed sepsis-induced heart dysfunction and improved survival in rats. This mitoK(ATP) channel blocker protected against cardiac contractile deficits and mitochondrial damage, suggesting Bax activation precedes channel opening in sepsis.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Sepsis Research
Background:
- Sepsis can cause severe cardiac dysfunction and mortality.
- Mitochondrial dysfunction plays a key role in sepsis-induced heart problems.
- 5-Hydroxydecanoic acid (5HD) is investigated as a potential therapeutic agent targeting mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels.
Purpose of the Study:
- To test if 5-Hydroxydecanoic acid (5HD) can reverse sepsis-induced cardiac dysfunction.
- To evaluate 5HD's effect on mitochondrial membrane permeability and survival in a rat sepsis model.
- To investigate the role of mitoK(ATP) channels in sepsis-induced myocardial injury.
Main Methods:
- Sepsis was induced in male Sprague-Dawley rats via cecal inoculum.
- Cardiac function was assessed using electrocardiography, measuring ejection fraction and cardiac output.
- Adult rat ventricular myocytes (ARVMs) were isolated to analyze Voltage Dependent Anion Channels (VDAC1), Bax, and cytochrome C levels.
- Mitochondrial membrane potential and contractility were measured in ARVMs treated with 5HD.
Main Results:
- 5HD administration significantly reduced sepsis-induced mortality.
- 5HD reversed the sepsis-associated decrease in ejection fraction and cardiac output.
- Treatment with 5HD restored contractility in septic adult rat ventricular myocytes (ARVMs).
- Sepsis led to downregulation of VDAC1, upregulation of Bax, and mitochondrial membrane potential collapse, all reversed by 5HD.
Conclusions:
- Bax activation appears to be an upstream event preceding mitoK(ATP) channel opening in sepsis.
- Inhibition of mitoK(ATP) channels by 5HD protects against sepsis-induced cardiac dysfunction.
- 5HD's protective effects involve maintaining mitochondrial membrane potential and reducing cytochrome C release.
