Sepsis is the body’s overwhelming response to an infection. It occurs when the immune system overreacts and damages the body’s own organs and tissues. Sepsis is life-threatening, yet about 1.9 million people in the United States survive it each year. More than half of sepsis-survivors face long-term complications such as problems with memory and thinking, prolonged tiredness, and muscle weakness. Researchers often link this lasting muscle weakness with reduced muscle mass during sepsis. However, symptoms sometimes persist even after the muscles have recovered, making it difficult to treat or prevent effectively.
To understand what causes long-term muscle weakness after recovery from severe sepsis, a team of scientists from the University of Kentucky used 16- to 18-month-old mice to approximate 55- to 60-year-old humans. They induced sepsis in the mice at day 0 by injecting a mixture of gut microbes into their abdomens. Then they checked the mice’s body temperatures every 12 hours to confirm they were low, a sign of active infection.
Starting 12 hours after injection, they gave the mice antibiotics twice daily for 5 days to prevent them from dying. Mice that survived past day 5 were classified as sepsis survivors. The team defined days 0 to 5 as the acute phase and days 14 to 70 as the chronic phase. For all their experiments, the researchers compared muscle health in mice with no sepsis, acute sepsis, and chronic sepsis.
The researchers tested the muscle attached to bones that enables voluntary movement, called skeletal muscle. They placed each mouse’s foot on a sensor and artificially stimulated the foot muscle to contract. The sensor measured contraction force as an indicator of muscle strength. They found that by day 3 of sepsis, the mice’s foot muscles were only about 60% as strong as they were before infection.
Once the researchers confirmed that the mice’s body temperatures had returned to normal and the infection had resolved, they took additional measurements at days 14 and 70. During this chronic phase, the mice’s muscles generated only about 30% of their original strength. The team concluded that muscle weakness developed after acute sepsis and persisted for months, even after the infection resolved.
The researchers previously found that the mice that survived severe sepsis and later developed lasting muscle weakness also had defects in their cells’ energy-producing structures, called mitochondria. To investigate whether sepsis damaged mitochondria in the mice’s skeletal muscle cells, the team measured a key energy-producing mitochondrial protein.
They dissected the mice’s leg muscles, placed thin sections of them on slides, and applied a colored marker that binds specifically to this protein. They counted the markers under a microscope to determine protein levels. They observed that the protein decreased by 8% by day 4 and by 20% by day 14. They concluded that mitochondrial defects were mild during the acute phase of sepsis but worsened in the chronic phase, which mirrored the progressive muscle worsening observed in sepsis survivors.
Because the mice’s mitochondria got more damaged over time, the team asked whether protecting their mitochondria could prevent long-term muscle weakness. To test this, they delivered a small protein drug, called SS-31, to their mitochondria. SS-31 shields mitochondria from damaging molecules and boosts energy production.
They treated one group of septic mice with SS-31 twice daily until day 5 and once daily until day 10. On day 21, they measured muscle strength in SS-31-treated mice, untreated septic mice, and healthy controls. SS-31-treated mice were about 15% stronger than untreated mice, reaching muscle strengths similar to those of mice that never had sepsis. On day 28, they measured mitochondrial protein and found that untreated mice had about 40% less, while SS-31-treated mice maintained normal levels like mice without sepsis. The scientists reported that giving SS-31 during acute sepsis can prevent chronic muscle weakness.
The authors stated that this is the first study to show that post-sepsis muscle weakness worsens after muscle repair, meaning that researchers should shift their focus from the acute to the chronic phase to study it. Since patients had increased mitochondrial abnormalities after acute sepsis, they also suggested that doctors could protect patients’ mitochondria with a prescribed drug like SS-31 during the acute phase to prevent post-sepsis muscle weakness.
