Post-sepsis chronic muscle weakness can be prevented by pharmacological protection of mitochondria.

Autor: Kingren MS; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Aging and Critical Care Research Laboratory, Department of Surgery, University of Kentucky, Lexington, KY, USA., Keeble AR; Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Physiology, University of Kentucky, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Galvan-Lara AM; Aging and Critical Care Research Laboratory, Department of Surgery, University of Kentucky, Lexington, KY, USA., Ogle JM; Aging and Critical Care Research Laboratory, Department of Surgery, University of Kentucky, Lexington, KY, USA., Ungvári Z; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Doctoral College/Department of Public Health, International Training Program in Geroscience, Semmelweis University, Budapest, Hungary., St Clair DK; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.; Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Butterfield TA; Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Rehabilitation Sciences, University of Kentucky, Lexington, KY, USA., Owen AM; Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Fry CS; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Physiology, University of Kentucky, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Patel SP; Department of Physiology, University of Kentucky, Lexington, KY, USA.; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA., Saito H; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA. hiroshi.saito@uky.edu.; Center for Muscle Biology, University of Kentucky, Lexington, KY, USA. hiroshi.saito@uky.edu.; Aging and Critical Care Research Laboratory, Department of Surgery, University of Kentucky, Lexington, KY, USA. hiroshi.saito@uky.edu.; Department of Physiology, University of Kentucky, Lexington, KY, USA. hiroshi.saito@uky.edu.; Markey Cancer Center, University of Kentucky, Lexington, KY, USA. hiroshi.saito@uky.edu.
Jazyk: angličtina
Zdroj: Molecular medicine (Cambridge, Mass.) [Mol Med] 2024 Nov 19; Vol. 30 (1), pp. 221. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1186/s10020-024-00982-w
Abstrakt: Background: Sepsis, mainly caused by bacterial infections, is the leading cause of in-patient hospitalizations. After discharge, most sepsis survivors suffer from long-term medical complications, particularly chronic skeletal muscle weakness. To investigate this medical condition in detail, we previously developed a murine severe sepsis-survival model that exhibits long-term post-sepsis skeletal muscle weakness. While mitochondrial abnormalities were present in the skeletal muscle of the sepsis surviving mice, the relationship between abnormal mitochondria and muscle weakness remained unclear. Herein, we aimed to investigate whether mitochondrial abnormalities have a causal role in chronic post-sepsis muscle weakness and could thereby serve as a therapeutic target.
Methods: Experimental polymicrobial abdominal sepsis was induced in 16-18 months old male and female mice using cecal slurry injection with subsequent antibiotic and fluid resuscitation. To evaluate the pathological roles of mitochondrial abnormalities in post-sepsis skeletal muscle weakness, we utilized a transgenic mouse strain overexpressing the mitochondria-specific antioxidant enzyme manganese superoxide dismutase (MnSOD). Following sepsis development in C57BL/6 mice, we evaluated the effect of the mitochondria-targeting synthetic tetrapeptide SS-31 in protecting mitochondria from sepsis-induced damage and preventing skeletal muscle weakness development. In vivo and in vitro techniques were leveraged to assess muscle function at multiple timepoints throughout sepsis development and resolution. Histological and biochemical analyses including bulk mRNA sequencing were used to detect molecular changes in the muscle during and after sepsis RESULTS: Our time course study revealed that post sepsis skeletal muscle weakness develops progressively after the resolution of acute sepsis and in parallel with the accumulation of mitochondrial abnormalities and changes in the mitochondria-related gene expression profile. Transgenic mice overexpressing MnSOD were protected from mitochondrial abnormalities and muscle weakness following sepsis. Further, pharmacological protection of mitochondria utilizing SS-31 during sepsis effectively prevented the later development of muscle weakness.
Conclusions: Our study revealed that the accumulation of mitochondrial abnormalities is the major cause of post-sepsis skeletal muscle weakness. Pharmacological protection of mitochondria during acute sepsis is a potential clinical treatment strategy to prevent post-sepsis muscle weakness.
Competing Interests: Declarations Ethics approval and consent to participate All animal experiments were conducted according to procedures described in our Animal Use Protocol #2009-0541 which is approved by the Institutional Animal Care and Use Committee at the University of Kentucky. Consent for publication Not Applicable. Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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