Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model

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

doi:10.7554/eLife.49920

Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model

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

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50 Scopus citations

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.

Original language	English
Article number	e49920
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.49920
State	Published - Dec 2019

Bibliographical note

Funding Information:
This project was mainly supported by NIH R01GM126181 (HS), R01 AG039732 (HS), R01 AG055359 (HS) and F31 GM117868 (AMO). The authors thank Ms Dana Napier and Karrie Jones with Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (supported by the grant P30 CA177558) for their assistance in sectioning skeletal muscle specimens; Jennifer Moylan with the Center for Clinical and Translational Science (supported by the grant UL1TR001998) for assistance with multiplex assay analysis; members of the Center for Muscle Biology, especially, Dr. Sarah White for her time sharing knowledge on fiber-type staining and quantification. Body composition analysis was conducted using echoMRI technology supported by grant P20 GM103527. Aperio ScanScope imaging was conducted with the help of the Markey Cancer Center and Alzheimer’s Disease Center supported by the grant P30 AG028383. Additionally, we thank Drs. Esther Dupont-Versteegden and Gerald Supinski for their helpful discussion in preparation for these experiments. Additionally, thanks to Ms. Donna Gil-breath of the Markey Cancer Center Research Communications Office for illustrative assistance.

Publisher Copyright:
© 2019, eLife Sciences Publications Ltd. All rights reserved.

ASJC Scopus subject areas

Neuroscience (all)
Biochemistry, Genetics and Molecular Biology (all)
Immunology and Microbiology (all)

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10.7554/eLife.49920

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Owen, A. M., Patel, S. P., Smith, J. D., Balasuriya, B. K., Mori, S. F., Hawk, G. S., Stromberg, A. J., Kuriyama, N., Kaneki, M., Rabchevsky, A. G., Butterfield, T. A., Esser, K. A., Peterson, C. A., Starr, M. E., & Saito, H. (2019). Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model. eLife, 8, Article e49920. https://doi.org/10.7554/eLife.49920

@article{ae7d7980f45342648fcc72f6a993739c,

title = "Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model",

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.",

author = "Owen, {Allison M.} and Patel, {Samir P.} and Smith, {Jeffrey D.} and Balasuriya, {Beverly K.} and Mori, {Stephanie F.} and Hawk, {Gregory S.} and Stromberg, {Arnold J.} and Naohide Kuriyama and Masao Kaneki and Rabchevsky, {Alexander G.} and Butterfield, {Timothy A.} and Esser, {Karyn A.} and Peterson, {Charlotte A.} and Starr, {Marlene E.} and Hiroshi Saito",

note = "Funding Information: This project was mainly supported by NIH R01GM126181 (HS), R01 AG039732 (HS), R01 AG055359 (HS) and F31 GM117868 (AMO). The authors thank Ms Dana Napier and Karrie Jones with Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (supported by the grant P30 CA177558) for their assistance in sectioning skeletal muscle specimens; Jennifer Moylan with the Center for Clinical and Translational Science (supported by the grant UL1TR001998) for assistance with multiplex assay analysis; members of the Center for Muscle Biology, especially, Dr. Sarah White for her time sharing knowledge on fiber-type staining and quantification. Body composition analysis was conducted using echoMRI technology supported by grant P20 GM103527. Aperio ScanScope imaging was conducted with the help of the Markey Cancer Center and Alzheimer{\textquoteright}s Disease Center supported by the grant P30 AG028383. Additionally, we thank Drs. Esther Dupont-Versteegden and Gerald Supinski for their helpful discussion in preparation for these experiments. Additionally, thanks to Ms. Donna Gil-breath of the Markey Cancer Center Research Communications Office for illustrative assistance. Publisher Copyright: {\textcopyright} 2019, eLife Sciences Publications Ltd. All rights reserved.",

year = "2019",

month = dec,

doi = "10.7554/eLife.49920",

language = "English",

volume = "8",

}

Owen, AM, Patel, SP, Smith, JD, Balasuriya, BK, Mori, SF, Hawk, GS, Stromberg, AJ, Kuriyama, N, Kaneki, M, Rabchevsky, AG , Butterfield, TA, Esser, KA, Peterson, CA, Starr, ME & Saito, H 2019, 'Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model', eLife, vol. 8, e49920. https://doi.org/10.7554/eLife.49920

TY - JOUR

T1 - Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model

AU - Owen, Allison M.

AU - Patel, Samir P.

AU - Smith, Jeffrey D.

AU - Balasuriya, Beverly K.

AU - Mori, Stephanie F.

AU - Hawk, Gregory S.

AU - Stromberg, Arnold J.

AU - Kuriyama, Naohide

AU - Kaneki, Masao

AU - Rabchevsky, Alexander G.

AU - Butterfield, Timothy A.

AU - Esser, Karyn A.

AU - Peterson, Charlotte A.

AU - Starr, Marlene E.

AU - Saito, Hiroshi

N1 - Funding Information: This project was mainly supported by NIH R01GM126181 (HS), R01 AG039732 (HS), R01 AG055359 (HS) and F31 GM117868 (AMO). The authors thank Ms Dana Napier and Karrie Jones with Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (supported by the grant P30 CA177558) for their assistance in sectioning skeletal muscle specimens; Jennifer Moylan with the Center for Clinical and Translational Science (supported by the grant UL1TR001998) for assistance with multiplex assay analysis; members of the Center for Muscle Biology, especially, Dr. Sarah White for her time sharing knowledge on fiber-type staining and quantification. Body composition analysis was conducted using echoMRI technology supported by grant P20 GM103527. Aperio ScanScope imaging was conducted with the help of the Markey Cancer Center and Alzheimer’s Disease Center supported by the grant P30 AG028383. Additionally, we thank Drs. Esther Dupont-Versteegden and Gerald Supinski for their helpful discussion in preparation for these experiments. Additionally, thanks to Ms. Donna Gil-breath of the Markey Cancer Center Research Communications Office for illustrative assistance. Publisher Copyright: © 2019, eLife Sciences Publications Ltd. All rights reserved.

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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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DO - 10.7554/eLife.49920

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VL - 8

JO - eLife

JF - eLife

M1 - e49920

ER -

Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model

Abstract

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ASJC Scopus subject areas

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