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Peroxisome proliferator‐activated receptor γ coactivator 1‐α overexpression improves angiogenic signalling potential of skeletal muscle‐derived extracellular vesicles

Authors :
Chris K. Kargl
Brian P. Sullivan
Derek Middleton
Andrew York
Lundon C. Burton
Jeffrey J. Brault
Shihuan Kuang
Timothy P. Gavin
Source :
Experimental Physiology, Vol 108, Iss 2, Pp 240-252 (2023)
Publication Year :
2023
Publisher :
Wiley, 2023.

Abstract

Abstract Skeletal muscle capillarization is proportional to muscle fibre mitochondrial content and oxidative capacity. Skeletal muscle cells secrete many factors that regulate neighbouring capillary endothelial cells (ECs), including extracellular vesicles (SkM‐EVs). Peroxisome proliferator‐activated receptor γ coactivator 1‐α (PGC‐1α) regulates mitochondrial biogenesis and the oxidative phenotype in skeletal muscle. Skeletal muscle PGC‐1α also regulates secretion of multiple angiogenic factors, but it is unknown whether PGC‐1α regulates SkM‐EV release, contents and angiogenic signalling potential. PGC‐1α was overexpressed via adenovirus in primary human myotubes. EVs were collected from PGC‐1α‐overexpressing myotubes (PGC‐EVs) as well as from green fluorescent protein‐overexpressing myotubes (GFP‐EVs), and from untreated myotubes. EV release and select mRNA contents were measured from EVs. Additionally, ECs were treated with EVs to measure angiogenic potential of EVs in normal conditions and following an oxidative stress challenge. PGC‐1α overexpression did not impact EV release but did elevate EV content of mRNAs for several antioxidant proteins (nuclear factor erythroid 2‐related factor 2, superoxide dismutase 2, glutathione peroxidase). PGC‐EV treatment of cultured human umbilical vein endothelial cells (HUVECs) increased their proliferation (+36.6%), tube formation (length: +28.1%; number: +25.7%) and cellular viability (+52.9%), and reduced reactive oxygen species levels (−41%) compared to GFP‐EVs. Additionally, PGC‐EV treatment protected against tube formation impairments and induction of cellular senescence following acute oxidative stress. Overexpression of PGC‐1α in human myotubes increases the angiogenic potential of SkM‐EVs. These angiogenic benefits coincided with increased anti‐oxidative capacity of recipient HUVECs. High PGC‐1α expression in skeletal muscle may prompt the release of SkM‐EVs that support vascular redox homeostasis and angiogenesis.

Details

Language :
English
ISSN :
1469445X and 09580670
Volume :
108
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Experimental Physiology
Publication Type :
Academic Journal
Accession number :
edsdoj.6de3d5d9ec1c4028a8ed480cbff72c12
Document Type :
article
Full Text :
https://doi.org/10.1113/EP090874