title: Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress.
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 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.
authors.affiliation: University of Jyväskylä, Department of Biology of Physical Activity, Neuromuscular Research Center, P.O. Box 35, FI-40014, Finland; Department of Physiology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland. Electronic address: juha.hulmi@jyu.fi.
authors.forename: Juha J
authors.initials: JJ
authors.lastname: Hulmi
authors.affiliation: University of Jyväskylä, Department of Biology of Physical Activity, Neuromuscular Research Center, P.O. Box 35, FI-40014, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Hentilä
authors.affiliation: Syracuse University, Department of Exercise Science, 820 Comstock Ave., 201 WB, Syracuse, NY, USA; Institute of Biomedicine, Physiology, University of Eastern Finland, Yliopistonranta 1 E, 70210 Kuopio, Finland.
authors.forename: Keith C
authors.initials: KC
authors.lastname: DeRuisseau
authors.affiliation: University of Jyväskylä, Department of Biology of Physical Activity, Neuromuscular Research Center, P.O. Box 35, FI-40014, Finland.
authors.forename: Bernardo M
authors.initials: BM
authors.lastname: Oliveira
authors.affiliation: University of Jyväskylä, Department of Biology of Physical Activity, Neuromuscular Research Center, P.O. Box 35, FI-40014, Finland.
authors.forename: Konstantinos G
authors.initials: KG
authors.lastname: Papaioannou
authors.affiliation: School of Health Sciences, University of Tampere, Medisiinarinkatu 3, FI-33014, Finland.
authors.forename: Reija
authors.initials: R
authors.lastname: Autio
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Rautpohjankatu 8, P.O. Box 35, FI-40014, Finland.
authors.forename: Urho M
authors.initials: UM
authors.lastname: Kujala
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: University of Jyväskylä, Department of Biology of Physical Activity, Neuromuscular Research Center, P.O. Box 35, FI-40014, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Kainulainen
authors.affiliation: Institute of Biomedicine, Physiology, University of Eastern Finland, Yliopistonranta 1 E, 70210 Kuopio, Finland.
authors.forename: Ayhan
authors.initials: A
authors.lastname: Korkmaz
authors.affiliation: Institute of Biomedicine, Physiology, University of Eastern Finland, Yliopistonranta 1 E, 70210 Kuopio, Finland.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Atalay
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation / Q000187:drug effects; D010805:Physical Conditioning, Animal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000074702:Proteostasis / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D030301:Activin Receptors, Type II; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D007141:Immunoglobulin Fc Fragments; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D056564:Sirtuin 1; D013879:Thioredoxins; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C574724:Atf6b protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C445672:Txnip protein, mouse; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; C425584:activin receptor type II-B; C470545:Sirt1 protein, mouse
keywords: ER stress; Myostatin; UPR; mdx