Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of survivors. Our data suggest that sustained mitochondrial dysfunction, rather than atrophy alone, underlies chronic sepsis-induced muscle weakness. This study emphasizes that conventional efforts that aim to recover muscle quantity will likely remain ineffective for regaining strength and improving quality of life after sepsis until deficiencies in muscle quality are addressed.
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This project was mainly supported by NIH R01GM126181 (HS), R01 AG039732 (HS), R01 AG055359 (HS) and F31 GM117868 (AMO).
National Institute of General Medical Sciences (F31 GM117868): Allison M Owen
National Institute of General Medical Sciences (R01 GM126181): Hiroshi Saito
National Institute on Aging (R01 AG055359): Hiroshi Saito
National Institute on Aging (R01 AG390732): Hiroshi Saito
National Institute of General Medical Sciences (R01 GM129532): Marlene E Starr
National Institute of General Medical Sciences (R01 GM117298): Masao Kaneki
National Institute of General Medical Sciences (R01 GM115552): Masao Kaneki
Shriners Hospitals for Children (85600): Masao Kaneki
Owen, Allison M.; Patel, Samir P.; Smith, Jeffrey D.; Balasuriya, Beverly K.; Mori, Stephanie F.; Hawk, Gregory S.; Stromberg, Arnold J.; Kuriyama, Naohide; Kaneki, Masao; Rabchevsky, Alexander G.; Butterfield, Timothy A.; Esser, Karyn A.; Peterson, Charlotte A.; Starr, Marlene E.; and Saito, Hiroshi, "Chronic Muscle Weakness and Mitochondrial Dysfunction in the Absence of Sustained Atrophy in a Preclinical Sepsis Model" (2019). Physiology Faculty Publications. 154.