Scalabrin, M orcid.org/0000-0001-6663-7088, Engman, V, Maccannell, A et al. (4 more authors) (2022) Temporal analysis of skeletal muscle remodelling post hindlimb ischemia reveals intricate autophagy regulation. American Journal of Physiology: Cell Physiology, 323 (6). C1601-C1610. ISSN 0363-6143
Abstract
Hind Limb Ischemia (HLI) is the most severe form of peripheral arterial disease, associated with a substantial reduction of limb blood flow that impairs skeletal muscle homeostasis to promote functional disability. The molecular regulators of HLI-induced muscle perturbations remain poorly defined. This study investigated whether perturbations in the molecular catabolic-autophagy signalling network were linked to temporal remodelling of skeletal muscle in HLI. HLI was induced via hindlimb ischemia (femoral artery ligation) and confirmed by Doppler echocardiography. Experiments were terminated at time points defined as early- (7 days; n=5) or late (28 days; n=5) stage HLI. Ischemic and non-ischemic (contralateral) limb muscles were compared. Ischemic vs. non-ischemic muscles demonstrated overt remodelling at early-HLI but normalised at late-HLI. Early-onset fibre atrophy was associated with excessive autophagy signalling in ischemic muscle: protein expression increased for Beclin-1, LC3 and p62 (p<0.05) but proteasome-dependent markers were reduced (p<0.05). Mitophagy signalling increased in early-stage HLI which aligned with an early and sustained loss of mitochondrial content (p<0.05). Upstream autophagy regulators Sestrins showed divergent responses during early-stage HLI (Sestrin2 increased while Sestrin1 decreased; p<0.05) in parallel to increased AMPK phosphorylation (p<0.05) and lower antioxidant enzyme expression. No changes were found in markers for mTORC1 signalling. These data indicate early-activation of the sestrin-AMPK signalling axis may regulate autophagy to stimulate rapid and overt muscle atrophy in HLI, which is normalised within weeks and accompanied by recovery of muscle mass. A complex interplay between Sestrins to regulate autophagy signalling during early-to-late muscle remodelling in HLI is likely.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022, American Journal of Physiology-Cell Physiology. This is an author produced version of an article published in American Journal of Physiology-Cell Physiology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Autophagy; Ischemia; Sestrins; Skeletal Muscle |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number BBSRC (Biotechnology & Biological Sciences Research Council) BB/T004231/1 MRC (Medical Research Council) MR/S025472/1 DSTL (Defence Science & Technology Laboratory) Not Known |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Nov 2022 10:26 |
Last Modified: | 17 Oct 2023 00:13 |
Status: | Published |
Publisher: | American Physiological Society |
Identification Number: | 10.1152/ajpcell.00174.2022 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:192557 |