Background: The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). Results: As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. Conclusion: We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.
Bibliographical noteFunding Information:
This study was supported by an infrastructure grant from The Netherlands Organization of Scientific Research (NWO): the Mouse Clinic for Cancer and Ageing (MCCA) as well as grants from The Netherlands Organization for Scientific Research (VICI grant 016.176.640 to JWJ, 645.001.001 to BMB), European Foundation for the Study of Diabetes (award supported by EFSD/Novo Nordisk to JWJ), a UMCG-GSMS PhD fellowship to MAVL, a grant from the University Medical Center Groningen to DJR and the De Cock-Hadders Foundation.
© 2021, The Author(s).
Copyright 2021 Elsevier B.V., All rights reserved.
- Insulin resistance
- Mitochondrial β-oxidation
- Skeletal muscle