Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity

Rodrigo W. Alves de Souza; David Gallo; Ghee Rye Lee; Eri Katsuyama; Alexa Schaufler; Janick Weber; Eva Csizmadia; George C. Tsokos; Lauren G. Koch; Steven L. Britton; Ulrik Wisløff; Patricia C. Brum; Leo E. Otterbein

doi:10.1016/j.celrep.2021.109018

Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity

Rodrigo W. Alves de Souza, David Gallo, Ghee Rye Lee, Eri Katsuyama, Alexa Schaufler, Janick Weber, Eva Csizmadia, George C. Tsokos, Lauren G. Koch, Steven L. Britton, Ulrik Wisløff, Patricia C. Brum, Leo E. Otterbein

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1^fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1^fl/fl mice show remarkable muscle atrophy compared to Hmox1^fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

Original language	English
Article number	109018
Journal	Cell Reports
Volume	35
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109018
Publication status	Published - Apr 20 2021
Externally published	Yes

Keywords

DAMP
exercise training
heme
heme oxygenase-1
hemopexin
mitochondrial dysfunction
muscle atrophy
muscle microtrauma
satellite cells

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2021.109018

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@article{39d349da1aea44958a2dc33a6339324b,

title = "Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity",

abstract = "Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.",

keywords = "DAMP, exercise training, heme, heme oxygenase-1, hemopexin, mitochondrial dysfunction, muscle atrophy, muscle microtrauma, satellite cells",

author = "{Alves de Souza}, {Rodrigo W.} and David Gallo and Lee, {Ghee Rye} and Eri Katsuyama and Alexa Schaufler and Janick Weber and Eva Csizmadia and Tsokos, {George C.} and Koch, {Lauren G.} and Britton, {Steven L.} and Ulrik Wisl{\o}ff and Brum, {Patricia C.} and Otterbein, {Leo E.}",

note = "Funding Information: This research was supported by grants from the Department of Defense ( W81XWH-16-0464 ); NIH ( R43GM125430 ); the National Football League Players Association; and ( R01DK119202 to L.E.O.); the S{\~a}o Paulo Research Foundation (FAPESP), Brazil ( 2015/228145 to P.C.B. and 14/25957-9 and 17/19954-5 to R.W.A.d.S.); the National Council for Scientific and Technological Development (CNPq), Brazil ( 306261/2016-2 to P.C.B.); and the American Heart Association ( 19CDA34760244 to R.W.A.d.S.). We thank Susan J. Hagen and the Electron Microscopy core at BIDMC ( NIH S10 OD019988 ). The LCR-HCR rat model system was supported by the Office of Research Infrastructure Programs (OD grant ROD012098A to L.G.K. and S.L.B.) from the NIH . Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = apr,

day = "20",

doi = "10.1016/j.celrep.2021.109018",

language = "English",

volume = "35",

journal = "Cell Reports",

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T1 - Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity

AU - Alves de Souza, Rodrigo W.

AU - Gallo, David

AU - Lee, Ghee Rye

AU - Katsuyama, Eri

AU - Schaufler, Alexa

AU - Weber, Janick

AU - Csizmadia, Eva

AU - Tsokos, George C.

AU - Koch, Lauren G.

AU - Britton, Steven L.

AU - Wisløff, Ulrik

AU - Brum, Patricia C.

AU - Otterbein, Leo E.

N1 - Funding Information: This research was supported by grants from the Department of Defense ( W81XWH-16-0464 ); NIH ( R43GM125430 ); the National Football League Players Association; and ( R01DK119202 to L.E.O.); the São Paulo Research Foundation (FAPESP), Brazil ( 2015/228145 to P.C.B. and 14/25957-9 and 17/19954-5 to R.W.A.d.S.); the National Council for Scientific and Technological Development (CNPq), Brazil ( 306261/2016-2 to P.C.B.); and the American Heart Association ( 19CDA34760244 to R.W.A.d.S.). We thank Susan J. Hagen and the Electron Microscopy core at BIDMC ( NIH S10 OD019988 ). The LCR-HCR rat model system was supported by the Office of Research Infrastructure Programs (OD grant ROD012098A to L.G.K. and S.L.B.) from the NIH . Publisher Copyright: © 2021 The Author(s)

PY - 2021/4/20

Y1 - 2021/4/20

N2 - Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

AB - Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

KW - DAMP

KW - exercise training

KW - heme

KW - heme oxygenase-1

KW - hemopexin

KW - mitochondrial dysfunction

KW - muscle atrophy

KW - muscle microtrauma

KW - satellite cells

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U2 - 10.1016/j.celrep.2021.109018

DO - 10.1016/j.celrep.2021.109018

M3 - Article

C2 - 33882313

AN - SCOPUS:85106085360

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 109018

ER -

Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity

Abstract

Keywords

ASJC Scopus subject areas

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