The impact on high-fat diet on skeletal muscle stem cell recruitment in CD36 deficient mice

Verpoorten, Sandrine

Medicine
December 2019

Thesis or dissertation


Rights
© 2019 Sandrine Verpoorten. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

The prevalence of obesity is a major risk factor for cardiovascular and metabolic diseases including impaired skeletal muscle regeneration. Given the importance of skeletal muscle function in the context of obesity, it is paramount to understand the underlying mechanisms of impaired muscle health. Since skeletal muscle regeneration is regulated by muscle stem cells, the so-called satellite cells (SC), this thesis aims to investigate the effects of diet-induced obesity (DIO) on SC function. This study provides evidence that SC function is impaired in obesity, possibly linked to ectopic lipid infiltration via the fatty acid translocase CD36. Ectopic lipid infiltration was further linked to altered gene expression involved in skeletal muscle redox homeostasis and lipid metabolism. The CD36-deficient mouse model (CD36 KO) used for this study provides, for the first time, evidence of improved redox signalling and decreased oxidative stress in skeletal muscle under high-fat diet conditions, potentially linked to an altered mitochondrial bioenergetic profile. CD36 KO mice showed improved skeletal muscle lipid metabolism but interestingly developed signs of hepatic steatosis when exposed to a high-fat diet. Furthermore, the observed impairment of SC function in WT animals on a high-fat diet was attenuated in CD36 deficiency. However, CD36 was also identified as a key regulator of SC terminal differentiation. CD36 KO mice showed impaired regeneration after acute skeletal muscle injury, possibly linked to the decreased SC differentiation capacity. Additionally, this study reports a decrease in macrophage infiltration in CD36 KO mice following skeletal muscle injury, possibly due to inefficient inflammation resolution, subsequently resulting in impaired regeneration.

This demonstrates that CD36 deficiency protects against DIO, intramuscular lipid deposition and oxidative stress but results in impaired SC differentiation, delayed muscle regeneration and hepatic steatosis. CD36 is a key mediator of fatty acid uptake in skeletal muscle, linking obesity with SC function and muscle regeneration.

Publisher
Hull York Medical School, The University of Hull and the University of York
Supervisor
Matsakas, Antonios
Sponsor (Organisation)
University of Hull; Hull York Medical School
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
3 MB
Identifier
hull:17806
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