Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants

Terence E. Ryan, Dean J. Yamaguchi, Cameron A. Schmidt, Tonya N. Zeczycki, Saame Raza Shaikh, Patricia Brophy, Thomas D. Green, Michael D. Tarpey, Reema Karnekar, Emma J. Goldberg, Genevieve C. Sparagna, Maria J. Torres, Brian H. Annex, P. Darrell Neufer, Espen E. Spangenburg, Joseph M. McClung

Research output: Contribution to journalArticle

Abstract

The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number21
DOIs
StatePublished - Nov 2 2018
Externally publishedYes

Fingerprint

Muscle Cells
Skeletal Muscle
Ischemia
Extremities
Ankle Brachial Index
Peripheral Arterial Disease
Energy Metabolism
Mitochondrial Genes
Amputation
Transcriptome
Stem Cells
Phenotype
Muscles
Messenger RNA
Mortality
Therapeutics
Genes

Keywords

  • Atherosclerosis
  • Cardiovascular disease
  • Metabolism
  • Skeletal muscle

Cite this

Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants. / Ryan, Terence E.; Yamaguchi, Dean J.; Schmidt, Cameron A.; Zeczycki, Tonya N.; Shaikh, Saame Raza; Brophy, Patricia; Green, Thomas D.; Tarpey, Michael D.; Karnekar, Reema; Goldberg, Emma J.; Sparagna, Genevieve C.; Torres, Maria J.; Annex, Brian H.; Neufer, P. Darrell; Spangenburg, Espen E.; McClung, Joseph M.

In: JCI Insight, Vol. 3, No. 21, 02.11.2018.

Research output: Contribution to journalArticle

Ryan, TE, Yamaguchi, DJ, Schmidt, CA, Zeczycki, TN, Shaikh, SR, Brophy, P, Green, TD, Tarpey, MD, Karnekar, R, Goldberg, EJ, Sparagna, GC, Torres, MJ, Annex, BH, Neufer, PD, Spangenburg, EE & McClung, JM 2018, 'Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants', JCI Insight, vol. 3, no. 21. https://doi.org/10.1172/jci.insight.123235
Ryan, Terence E. ; Yamaguchi, Dean J. ; Schmidt, Cameron A. ; Zeczycki, Tonya N. ; Shaikh, Saame Raza ; Brophy, Patricia ; Green, Thomas D. ; Tarpey, Michael D. ; Karnekar, Reema ; Goldberg, Emma J. ; Sparagna, Genevieve C. ; Torres, Maria J. ; Annex, Brian H. ; Neufer, P. Darrell ; Spangenburg, Espen E. ; McClung, Joseph M. / Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants. In: JCI Insight. 2018 ; Vol. 3, No. 21.
@article{2ee52ba25b7c4e0cb8f54cd9eae86e45,
title = "Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants",
abstract = "The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.",
keywords = "Atherosclerosis, Cardiovascular disease, Metabolism, Skeletal muscle",
author = "Ryan, {Terence E.} and Yamaguchi, {Dean J.} and Schmidt, {Cameron A.} and Zeczycki, {Tonya N.} and Shaikh, {Saame Raza} and Patricia Brophy and Green, {Thomas D.} and Tarpey, {Michael D.} and Reema Karnekar and Goldberg, {Emma J.} and Sparagna, {Genevieve C.} and Torres, {Maria J.} and Annex, {Brian H.} and Neufer, {P. Darrell} and Spangenburg, {Espen E.} and McClung, {Joseph M.}",
year = "2018",
month = "11",
day = "2",
doi = "10.1172/jci.insight.123235",
language = "English (US)",
volume = "3",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "21",

}

TY - JOUR

T1 - Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants

AU - Ryan, Terence E.

AU - Yamaguchi, Dean J.

AU - Schmidt, Cameron A.

AU - Zeczycki, Tonya N.

AU - Shaikh, Saame Raza

AU - Brophy, Patricia

AU - Green, Thomas D.

AU - Tarpey, Michael D.

AU - Karnekar, Reema

AU - Goldberg, Emma J.

AU - Sparagna, Genevieve C.

AU - Torres, Maria J.

AU - Annex, Brian H.

AU - Neufer, P. Darrell

AU - Spangenburg, Espen E.

AU - McClung, Joseph M.

PY - 2018/11/2

Y1 - 2018/11/2

N2 - The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.

AB - The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.

KW - Atherosclerosis

KW - Cardiovascular disease

KW - Metabolism

KW - Skeletal muscle

UR - http://www.scopus.com/inward/record.url?scp=85063242742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063242742&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.123235

DO - 10.1172/jci.insight.123235

M3 - Article

C2 - 30385731

AN - SCOPUS:85063242742

VL - 3

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 21

ER -