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Heme-induced oxidation of cysteine groups of myofilament proteins leads to contractile dysfunction of permeabilized human skeletal muscle fibres

Alvarado, Gerardo ; Tóth, Attila ; Csősz, Éva ; Kalló, Gergő ; Dankó, Katalin ; Csernátony, Zoltán ; Smith, Ann ; Gram, Magnus LU orcid ; Akerström, Bo LU and Édes, István , et al. (2020) In International Journal of Molecular Sciences 21(21).
Abstract

Background: Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Methods: Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. Results: A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin,... (More)

Background: Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Methods: Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. Results: A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). Conclusions: These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Chronic heart failure, Contractile dysfunction, Heme, Hemopexin, Oxidation, Skeletal muscle fibre, Skeletal muscle myopathy, Sulfenic acid formation, Sulfhydryl groups, α1-microglobulin
in
International Journal of Molecular Sciences
volume
21
issue
21
article number
8172
pages
19 pages
publisher
MDPI AG
external identifiers
  • pmid:33142923
  • scopus:85094855183
ISSN
1661-6596
DOI
10.3390/ijms21218172
language
English
LU publication?
yes
id
9f997d3e-5128-4193-8716-70e1101dcd8a
date added to LUP
2020-11-16 07:43:25
date last changed
2024-03-20 20:01:59
@article{9f997d3e-5128-4193-8716-70e1101dcd8a,
  abstract     = {{<p>Background: Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Methods: Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. Results: A single heme exposure (20 µM) to muscle fibres decreased Ca<sup>2+</sup>-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca<sup>2+</sup>-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). Conclusions: These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.</p>}},
  author       = {{Alvarado, Gerardo and Tóth, Attila and Csősz, Éva and Kalló, Gergő and Dankó, Katalin and Csernátony, Zoltán and Smith, Ann and Gram, Magnus and Akerström, Bo and Édes, István and Balla, György and Papp, Zoltán and Balla, József}},
  issn         = {{1661-6596}},
  keywords     = {{Chronic heart failure; Contractile dysfunction; Heme; Hemopexin; Oxidation; Skeletal muscle fibre; Skeletal muscle myopathy; Sulfenic acid formation; Sulfhydryl groups; α1-microglobulin}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Heme-induced oxidation of cysteine groups of myofilament proteins leads to contractile dysfunction of permeabilized human skeletal muscle fibres}},
  url          = {{http://dx.doi.org/10.3390/ijms21218172}},
  doi          = {{10.3390/ijms21218172}},
  volume       = {{21}},
  year         = {{2020}},
}