Sepsis is an extreme reaction of the body to infection. This occurs when the immune system overreacts, causing damage to its own organs and tissues. While sepsis can be life-threatening, around 1.9 million individuals in the United States recover from sepsis each year. However, more than half of these survivors endure long-term complications, such as memory issues, fatigue, and muscle weakness. Research commonly links persistent muscle weakness to muscle mass loss during sepsis, yet symptoms may linger even after muscle recovery, complicating treatment and prevention efforts.

To investigate the underlying causes of ongoing muscle weakness post-severe sepsis, scientists at the University of Kentucky used 16- to 18-month-old mice, equivalent to human ages of 55 to 60 years. They induced sepsis on day 0 by injecting abdominal mixes of intestinal bacteria. Body temperatures were monitored every 12 hours to confirm active infection.

To prevent fatalities, the mice received antibiotics twice daily for 5 days, starting 12 hours post-injection. Mice that survived beyond day 5 were categorized as sepsis survivors. The initial 5 days were termed the acute stage, while days 14 to 70 comprised the chronic phase. Throughout the study, muscle health in non-septic, acutely septic, and chronically septic mice was compared.

The researchers focused on voluntary movement muscles, known as skeletal muscles. They placed each mouse’s foot on a sensor to artificially stimulate the muscles and measure contraction force as an indicator of muscle strength. By day 3 of sepsis, the mice’s leg muscles exhibited only 60% of their pre-infection strength.

Further measurements on days 14 and 70 confirmed that, despite normalizing body temperatures and resolving infections, the mice’s muscles produced only about 30% of their original strength. The researchers concluded that muscle weakness initiated during acute sepsis could persist for several months following infection resolution.

Prior research revealed that mice surviving severe sepsis and experiencing persistent muscle weakness also demonstrated defects in their cellular energy factories, known as mitochondria. To assess whether sepsis damaged mitochondrial function in mouse skeletal muscle cells, the team measured key energy-producing mitochondrial proteins.

They dissected a mouse leg muscle, placed thin sections on slides, and applied a specific colored marker binding to these proteins. Protein levels were quantified by examining markers under a microscope. Results showed an 8% decrease by day 4 and a 20% decrease by day 14. The study indicated that mitochondrial defects were mild during the acute sepsis phase but grew worse in the chronic phase, aligning with the observed muscle deterioration in sepsis survivors.

As mitochondrial damage in mice increased over time, the researchers hypothesized that protecting mitochondria could prevent chronic muscle weakness. They experimented with a small protein drug called SS-31, designed to guard mitochondria from damaging agents and enhance energy production.

One group of septic mice received SS-31 twice daily until day 5 and once daily until day 10. On day 21, muscle strength was evaluated in mice treated with SS-31, untreated septic mice, and healthy controls. SS-31-treated mice exhibited approximately 15% greater muscle strength than untreated counterparts, reaching levels comparable to healthy mice. Measurements of mitochondrial proteins on day 28 revealed a 40% reduction in untreated mice, while SS-31-treated mice maintained typical protein levels akin to non-septic mice. These findings suggest that administering SS-31 during acute sepsis may effectively prevent chronic muscle weakness.

The authors noted that this is the first study to demonstrate that post-sepsis muscle weakness intensifies post-recovery, necessitating a shift in focus from the acute phase to the chronic phase. They also proposed that clinicians could potentially protect patients’ mitochondria using drugs like SS-31 during the acute phase to mitigate post-sepsis muscle weakness, given the increased mitochondrial abnormalities in patients following severe sepsis.

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