Diabetes Worsens Skeletal Muscle Mitochondrial Function, Oxidative Stress, and Apoptosis After Lower-Limb Ischemia-Reperfusion: Implication of the RISK and SAFE Pathways?

Diabetic patients respond poorly to revascularization for peripheral arterial disease (PAD) but the underlying mechanisms are not well understood. We aimed to determine whether diabetes worsens ischemia-reperfusion (IR)-induced muscle dysfunction and the involvement of endogenous protective kinases...

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Veröffentlicht in:Frontiers in physiology Jg. 9; S. 579
Hauptverfasser: Pottecher, Julien, Adamopoulos, Chris, Lejay, Anne, Bouitbir, Jamal, Charles, Anne-Laure, Meyer, Alain, Singer, Mervyn, Wolff, Valerie, Diemunsch, Pierre, Laverny, Gilles, Metzger, Daniel, Geny, Bernard
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers 22.05.2018
Frontiers Media S.A
Schlagworte:
Cellular Biology
diabetes
ischemia-reperfusion
Life Sciences
mitochondria
muscles
peripheral arterial disease
Physiology
protective kinases
Subcellular Processes
peripheral arterial disease
muscles
ischemia-reperfusion
diabetes
mitochondria
protective kinases
ISSN:1664-042X, 1664-042X
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Zusammenfassung:Diabetic patients respond poorly to revascularization for peripheral arterial disease (PAD) but the underlying mechanisms are not well understood. We aimed to determine whether diabetes worsens ischemia-reperfusion (IR)-induced muscle dysfunction and the involvement of endogenous protective kinases in this process. Streptozotocin-induced diabetic and non-diabetic rats were randomized to control or to IR injury (3 h of aortic cross-clamping and 2 h of reperfusion). Mitochondrial respiration, reactive oxygen species (ROS) production, protein levels of superoxide dismutase (SOD2) and endogenous protective kinases (RISK and SAFE pathways) were investigated in rat gastrocnemius, together with upstream (GSK-3β) and downstream (cleaved caspase-3) effectors of apoptosis. Although already impaired when compared to non-diabetic controls at baseline, the decline in mitochondrial respiration after IR was more severe in diabetic rats. In diabetic animals, IR-triggered oxidative stress (increased ROS production and reduced SOD2 levels) and effectors of apoptosis (reduced GSK-3β inactivation and higher cleaved caspase-3 levels) were increased to a higher level than in the non-diabetics. IR had no effect on the RISK pathway in non-diabetics and diabetic rats, but increased STAT 3 only in the latter. Type 1 diabetes worsens IR-induced skeletal muscle injury, endogenous protective pathways not being efficiently stimulated.
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PMCID: PMC5972292
Reviewed by: Adam Salmon, University of Texas Health Science Center San Antonio, United States; Pasquale Pagliaro, Università degli Studi di Torino, Italy
This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology
Edited by: Agustín Guerrero-Hernández, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico
ISSN:1664-042X
1664-042X
DOI:10.3389/fphys.2018.00579