Sepsis
is an overwhelming response by the body to infection, occurring when the immune system overreacts and harms its own organs and tissues. Despite its life-threatening nature, around 1.9 million individuals in the United States survive sepsis each year. However, over half of these survivors experience long-term complications such as cognitive issues, chronic fatigue, and muscle weakness. This persistent muscle weakness is often linked to muscle mass loss during sepsis, yet symptoms may linger even after muscle recovery, complicating effective treatment and prevention.

To investigate the causes of chronic muscle weakness post-sepsis recovery, a research team at the University of Kentucky studied 16- to 18-month-old mice, akin to human ages of 55 to 60 years. They induced sepsis on day 0 by injecting a mixture of intestinal bacteria into the abdomen of the mice, monitoring their body temperatures every 12 hours to detect signs of active infection.

To prevent mortality, the mice received antibiotics twice daily for 5 days, starting 12 hours post-injection. Surviving mice beyond day 5 were categorized as sepsis survivors, with days 0 to 5 defined as the acute stage and days 14 to 70 comprising the chronic phase. The team compared muscle health across mice with no sepsis, those in the acute phase, and those in the chronic phase.

The researchers focused on skeletal muscles, responsible for voluntary movements. They placed each mouse’s foot over a sensor and stimulated the muscles to contract, measuring contraction force as an indicator of muscle strength. By the third day of sepsis, the leg muscles exhibited only about 60% of their pre-infection strength.

Additional measurements taken on days 14 and 70 confirmed that, despite normal body temperatures and resolved infections, the mice’s muscle strength was only 30% of its original capacity. This indicates that muscle weakness developed post-acute sepsis and persisted for months after the infection.

The researchers previously discovered that mice that survived severe sepsis and later experienced persistent muscle weakness exhibited defects in mitochondria, the energy-producing structures in cells. They measured key mitochondrial proteins to assess damage in mouse skeletal muscle cells.

A mouse leg muscle was dissected, thin sections were placed on slides, and a specific marker was applied to bind to the proteins. Under a microscope, researchers counted markers to measure protein levels, finding an 8% decrease by day 4 and a 20% decrease by day 14. This suggests that mitochondrial defects worsened from mild during the acute phase to more severe during the chronic phase, paralleling muscle deterioration in sepsis survivors.

Given the progressive mitochondrial damage, researchers evaluated whether protecting mitochondria could prevent long-term muscle weakness. They delivered a small protein drug called SS-31 to the mitochondria, which guards these structures against harmful molecules and enhances energy production.

One group of septic mice was treated with SS-31 twice a day until day 5 and once a day until day 10. By day 21, muscle strength was assessed in SS-31-treated mice, untreated septic mice, and healthy controls. Mice receiving SS-31 demonstrated approximately 15% greater strength compared to untreated subjects, achieving muscle levels akin to those that had never experienced sepsis. Measurement of mitochondrial proteins on day 28 showed a 40% reduction in untreated mice, while SS-31-treated mice maintained normal protein levels, similar to non-septic mice. This indicates that SS-31 can safeguard against chronic muscle weakness post-sepsis.

The authors highlighted that this is the first study to demonstrate that post-sepsis muscle weakness can worsen after muscle repair, emphasizing the need for researchers to shift their focus from the acute to the chronic phase. They also suggested that clinicians could consider protecting patients’ mitochondria with drugs like SS-31 during the acute phase to mitigate the risk of post-sepsis muscle weakness, as mitochondrial abnormalities have been observed in patients following acute sepsis.

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