Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle

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dc.contributor.authorSilva, Kleiton Augusto Santosen
dc.contributor.authorGhiarone, Thaysaen
dc.contributor.authorGrant, DeAnaen
dc.contributor.authorWhite, Tommien
dc.contributor.authorFrisard, Madlyn I.en
dc.contributor.authorChandrasekar, Bysanien
dc.contributor.authorDelafontaine, Patriceen
dc.contributor.authorYoshida, Tadashien
dc.contributor.authorSchreiber, Kathyen
dc.contributor.authorSukhanov, Sergiyen
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2020-01-05T11:24:04Zen
dc.date.available2020-01-05T11:24:04Zen
dc.date.issued2019-06-01en
dc.date.updated2020-01-05T11:24:00Zen
dc.description.abstractAngiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5=-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels.en
dc.description.versionPublished versionen
dc.format.extentPages 1550-1552en
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.issue6en
dc.identifier.orcidFrisard, Madlyn [0000-0002-9284-9460]en
dc.identifier.urihttp://hdl.handle.net/10919/96293en
dc.identifier.volume126en
dc.language.isoenen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject06 Biological Sciencesen
dc.subject11 Medical and Health Sciencesen
dc.subjectPhysiologyen
dc.titleAngiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscleen
dc.title.serialJournal of Applied Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Human Nutrition, Foods, & Exerciseen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutesen

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