Loss of CD36 protects against diet‐induced obesity but results in impaired muscle stem cell function, delayed muscle regeneration and hepatic steatosis

Abstract

Aim The prevalence of obesity is a major risk factor for cardiovascular and metabolic diseases including impaired skeletal muscle regeneration. Since skeletal muscle regenerative capacity is regulated by satellite cells, we aimed to investigate whether a high‐fat diet impairs satellite cell function and whether this is linked to fatty acid uptake via CD36. We also aimed to determine whether loss of CD36 impacts on muscle redox homeostasis and skeletal muscle regenerative capacity. Methods We studied the impact of a high‐fat diet and CD36 deficiency on murine skeletal muscle morphology, redox homeostasis, satellite cell function, bioenergetics and lipid accumulation in the liver. We also determined the effect of CD36 deficiency on skeletal muscle regeneration. Results High‐fat diet increased body weight, intramuscular lipid accumulation and oxidative stress in wild‐type mice that were significantly mitigated in CD36‐deficient mice. High‐fat diet and CD36 deficiency independently attenuated satellite cell function on single fibres and myogenic capacity on primary satellite cells. CD36 deficiency resulted in delayed skeletal muscle regeneration following acute injury with cardiotoxin. CD36‐deficient and wild‐type primary satellite cells had distinct bioenergetic profiles in response to palmitate. High‐fat diet induced hepatic steatosis in both genotypes that was more pronounced in the CD36‐deficient mice. Conclusion This study demonstrates that CD36 deficiency protects against diet‐induced obesity, intramuscular lipid deposition and oxidative stress but results in impaired muscle satellite cell function, delayed muscle regeneration and hepatic steatosis. CD36 is a key mediator of fatty acid uptake in skeletal muscle, linking obesity with satellite cell function and muscle regeneration.

Influence of Obesity on the Organization of the Extracellular Matrix and Satellite Cell Functions After Combined Muscle and Thorax Trauma in C57BL/6J Mice

“…Although it has been shown that there exists a negative correlation between obesity and the outcome after combined trauma injury, the molecular mechanisms remain unclear. Besides adverse effects and complication in the lung, obesity has also been shown to influence the regeneration of skeletal muscle ( Brown and Kuk, 2015 ; D’Souza et al, 2015 ; Li et al, 2020 ; Verpoorten et al, 2020 ).…”

Adipose tissue—more than just fat

“…A number of articles addressing basic mechanisms related to obesity have recently appeared in Acta physiologica. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] One area of clinical relevance for obese patients is the immune system. Duan et al 20 recapitulate the connections between a high-fat diet and diseases.…”

“…18 In addition, CD36, a mediator for fatty acid uptake in skeletal muscle, was identified as a link between obesity and skeletal muscle redox homeostasis and muscle regeneration. 19 When Verpoorten et al fed mice with a high-fat diet, the CD36 deficient group occurred to be protected from weight-gain in comparison to the wild-type mice. But perturbed satellite cell function in this group also did provoke negative effects on muscle homeostasis and regeneration.…”

“…A precise understanding of these effects is necessary to comprehend specific needs of obese patients. A number of articles addressing basic mechanisms related to obesity have recently appeared in Acta physiologica …”

“…Mutations in the non‐selective monovalent cation channel TRPM5 have been associated with type II diabetes and metabolic syndrome . In addition, CD36, a mediator for fatty acid uptake in skeletal muscle, was identified as a link between obesity and skeletal muscle redox homeostasis and muscle regeneration . When Verpoorten et al fed mice with a high‐fat diet, the CD36 deficient group occurred to be protected from weight‐gain in comparison to the wild‐type mice.…”