Chronic Muscle Weakness and Mitochondrial Dysfunction in the Absence of Sustained Atrophy in a Preclinical Sepsis Model

Authors

Allison M. Owen, University of KentuckyFollow
Samir P. Patel, University of KentuckyFollow
Jeffrey D. Smith, University of KentuckyFollow
Beverly K. Balasuriya, University of KentuckyFollow
Stephanie F. Mori, University of KentuckyFollow
Gregory S. Hawk, University of KentuckyFollow
Arnold J. Stromberg, University of KentuckyFollow
Naohide Kuriyama, Massachusetts General Hospital
Masao Kaneki, Massachusetts General Hospital
Alexander G. Rabchevsky, University of KentuckyFollow
Timothy A. Butterfield, University of KentuckyFollow
Karyn A. Esser, University of KentuckyFollow
Charlotte A. Peterson, University of KentuckyFollow
Marlene E. Starr, University of KentuckyFollow
Hiroshi Saito, University of KentuckyFollow

Abstract

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.

Document Type

Article

Publication Date

12-3-2019

Notes/Citation Information

Published in eLife, v. 8, e49920, p. 1-25.

© 2019, Owen et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.7554/eLife.49920.001

Funding Information

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

Repository Citation

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.
https://uknowledge.uky.edu/physiology_facpub/154