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Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress

Hulmi, Juha J.; Hentilä, Jaakko; DeRuisseau, Keith C.; Oliveira, Bernardo M.; Papaioannou, Konstantinos G.; Autio, Reija; Kujala, Urho M.; Ritvos, Olli; Kainulainen, Heikki and Korkmaz, Ayhan, et al. (2016) In Free Radical Biology and Medicine 99. p.308-322
Abstract

Protein homeostasis in cells, proteostasis, is maintained through several integrated processes and pathways and its dysregulation may mediate pathology in many diseases including Duchenne muscular dystrophy (DMD). Oxidative stress, heat shock proteins, endoplasmic reticulum (ER) stress and its response, i.e. unfolded protein response (UPR), play key roles in proteostasis but their involvement in the pathology of DMD are largely unknown. Moreover, exercise and activin receptor IIB blocking are two strategies that may be beneficial to DMD muscle, but studies to examine their effects on these proteostasis pathways are lacking. Therefore, these pathways were examined in the muscle of mdx mice, a model of DMD, under basal conditions and in... (More)

Protein homeostasis in cells, proteostasis, is maintained through several integrated processes and pathways and its dysregulation may mediate pathology in many diseases including Duchenne muscular dystrophy (DMD). Oxidative stress, heat shock proteins, endoplasmic reticulum (ER) stress and its response, i.e. unfolded protein response (UPR), play key roles in proteostasis but their involvement in the pathology of DMD are largely unknown. Moreover, exercise and activin receptor IIB blocking are two strategies that may be beneficial to DMD muscle, but studies to examine their effects on these proteostasis pathways are lacking. Therefore, these pathways were examined in the muscle of mdx mice, a model of DMD, under basal conditions and in response to seven weeks of voluntary exercise and/or activin receptor IIB ligand blocking using soluble activin receptor-Fc (sAcvR2B-Fc) administration. In conjunction with reduced muscle strength, mdx muscle displayed greater levels of UPR/ER-pathway indicators including greater protein levels of IRE1α, PERK and Atf6b mRNA. Downstream to IRE1α and PERK, spliced Xbp1 mRNA and phosphorylation of eIF2α, were also increased. Most of the cytoplasmic and ER chaperones and mitochondrial UPR markers were unchanged in mdx muscle. Oxidized glutathione was greater in mdx and was associated with increases in lysine acetylated proteome and phosphorylated sirtuin 1. Exercise increased oxidative stress when performed independently or combined with sAcvR2B-Fc administration. Although neither exercise nor sAcvR2B-Fc administration imparted a clear effect on ER stress/UPR pathways or heat shock proteins, sAcvR2B-Fc administration increased protein expression levels of GRP78/BiP, a triggering factor for ER stress/UPR activation and TxNIP, a redox-regulator of ER stress-induced inflammation. In conclusion, the ER stress and UPR are increased in mdx muscle. However, these processes are not distinctly improved by voluntary exercise or blocking activin receptor IIB ligands and thus do not appear to be optimal therapeutic choices for improving proteostasis in DMD.

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published
subject
keywords
ER stress, mdx, Myostatin, UPR
in
Free Radical Biology and Medicine
volume
99
pages
15 pages
publisher
Elsevier
external identifiers
  • Scopus:84983651853
ISSN
0891-5849
DOI
10.1016/j.freeradbiomed.2016.08.017
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English
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no
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8b5b894c-accc-4991-a3a7-871eb605eddd
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2016-09-29 16:12:39
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2016-11-14 10:22:43
@misc{8b5b894c-accc-4991-a3a7-871eb605eddd,
  abstract     = {<p>Protein homeostasis in cells, proteostasis, is maintained through several integrated processes and pathways and its dysregulation may mediate pathology in many diseases including Duchenne muscular dystrophy (DMD). Oxidative stress, heat shock proteins, endoplasmic reticulum (ER) stress and its response, i.e. unfolded protein response (UPR), play key roles in proteostasis but their involvement in the pathology of DMD are largely unknown. Moreover, exercise and activin receptor IIB blocking are two strategies that may be beneficial to DMD muscle, but studies to examine their effects on these proteostasis pathways are lacking. Therefore, these pathways were examined in the muscle of mdx mice, a model of DMD, under basal conditions and in response to seven weeks of voluntary exercise and/or activin receptor IIB ligand blocking using soluble activin receptor-Fc (sAcvR2B-Fc) administration. In conjunction with reduced muscle strength, mdx muscle displayed greater levels of UPR/ER-pathway indicators including greater protein levels of IRE1α, PERK and Atf6b mRNA. Downstream to IRE1α and PERK, spliced Xbp1 mRNA and phosphorylation of eIF2α, were also increased. Most of the cytoplasmic and ER chaperones and mitochondrial UPR markers were unchanged in mdx muscle. Oxidized glutathione was greater in mdx and was associated with increases in lysine acetylated proteome and phosphorylated sirtuin 1. Exercise increased oxidative stress when performed independently or combined with sAcvR2B-Fc administration. Although neither exercise nor sAcvR2B-Fc administration imparted a clear effect on ER stress/UPR pathways or heat shock proteins, sAcvR2B-Fc administration increased protein expression levels of GRP78/BiP, a triggering factor for ER stress/UPR activation and TxNIP, a redox-regulator of ER stress-induced inflammation. In conclusion, the ER stress and UPR are increased in mdx muscle. However, these processes are not distinctly improved by voluntary exercise or blocking activin receptor IIB ligands and thus do not appear to be optimal therapeutic choices for improving proteostasis in DMD.</p>},
  author       = {Hulmi, Juha J. and Hentilä, Jaakko and DeRuisseau, Keith C. and Oliveira, Bernardo M. and Papaioannou, Konstantinos G. and Autio, Reija and Kujala, Urho M. and Ritvos, Olli and Kainulainen, Heikki and Korkmaz, Ayhan and Atalay, Mustafa},
  issn         = {0891-5849},
  keyword      = {ER stress,mdx,Myostatin,UPR},
  language     = {eng},
  month        = {10},
  pages        = {308--322},
  publisher    = {ARRAY(0x80e59b8)},
  series       = {Free Radical Biology and Medicine},
  title        = {Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress},
  url          = {http://dx.doi.org/10.1016/j.freeradbiomed.2016.08.017},
  volume       = {99},
  year         = {2016},
}