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Eicosapentaenoic and Docosahexaenoic Acid-Enriched High Fat Diet Delays Skeletal Muscle Degradation in Mice

View Article: PubMed Central - PubMed

ABSTRACT

Low-grade chronic inflammatory conditions such as ageing, obesity and related metabolic disorders are associated with deterioration of skeletal muscle (SkM). Human studies have shown that marine fatty acids influence SkM function, though the underlying mechanisms of action are unknown. As a model of diet-induced obesity, we fed C57BL/6J mice either a high fat diet (HFD) with purified marine fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (HFD-ED), a HFD with corn oil, or normal mouse chow for 8 weeks; and used transcriptomics to identify the molecular effects of EPA and DHA on SkM. Consumption of ED-enriched HFD modulated SkM metabolism through increased gene expression of mitochondrial β-oxidation and slow-fiber type genes compared with HFD-corn oil fed mice. Furthermore, HFD-ED intake increased nuclear localization of nuclear factor of activated T-cells (Nfatc4) protein, which controls fiber-type composition. This data suggests a role for EPA and DHA in mitigating some of the molecular responses due to a HFD in SkM. Overall, the results suggest that increased consumption of the marine fatty acids EPA and DHA may aid in the prevention of molecular processes that lead to muscle deterioration commonly associated with obesity-induced low-grade inflammation.

No MeSH data available.


Schematic representation of the role of ED—enriched HFD on the gSkM transcriptome and modulation of ageing and/or obesity-induced sarcopenia in C57Bl/6J mice. Briefly, ED enriched HFD downregulates glucose synthase kinase 3 beta (Gsk3β) that phosphorylates nuclear factor of activated T cells (Nfatc4) and excludes it from entering into the nucleus. It also increases cytosolic calcium concentrations that in turn regulate calcineurin that then dephosphorylates Nfat allowing its localization in the nucleus. Upon localization, Nfat forms complex with myogenin (Myog) to turn on slow-fiber-type specific gene-program for e.g., Troponin C1. Pgc1α, a known master regulator of mitochondrial biogenesis was also seen upregulated by ED enriched HFD that could act upon multiple targets, one of which regulating dephosphorylation of Nfatc4 isoforms and its further nuclear localization.
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nutrients-08-00543-f004: Schematic representation of the role of ED—enriched HFD on the gSkM transcriptome and modulation of ageing and/or obesity-induced sarcopenia in C57Bl/6J mice. Briefly, ED enriched HFD downregulates glucose synthase kinase 3 beta (Gsk3β) that phosphorylates nuclear factor of activated T cells (Nfatc4) and excludes it from entering into the nucleus. It also increases cytosolic calcium concentrations that in turn regulate calcineurin that then dephosphorylates Nfat allowing its localization in the nucleus. Upon localization, Nfat forms complex with myogenin (Myog) to turn on slow-fiber-type specific gene-program for e.g., Troponin C1. Pgc1α, a known master regulator of mitochondrial biogenesis was also seen upregulated by ED enriched HFD that could act upon multiple targets, one of which regulating dephosphorylation of Nfatc4 isoforms and its further nuclear localization.

Mentions: In this study, we have shown that HFD-ED improves muscle metabolism and promotes a switch to slow-fiber type compared to HFD-corn oil. HFD-ED improves metabolism of fatty acids in gSkM by upregulating expression of genes coding for proteins involved in fatty acid β-oxidation, the Krebs cycle and oxidative phosphorylation. Lipid analysis shows that the HFD-ED fed animals had lower total fatty acid content compared to HFD-corn oil and control diet fed animals. Reduced ectopic fat accumulation in HFD-ED compared with HFD-corn oil fed animals suggests a physiological effect of EPA and DHA on muscle metabolic health. Higher expression of the genes involved in muscle contraction was found in gSkM of HFD-ED fed animals compared with HFD-corn oil fed animals. Western blot analysis showed reduced Acc protein levels in gSkM of HFD-ED fed animals compared with HFD-corn oil, confirming gene expression results. Acc is an inhibitor of fatty acid β-oxidation in mitochondria and the lower levels shows increase in mitochondrial fatty acid β-oxidation. In addition, increased Tnnc1 levels suggest increased muscle contraction in gSkM of HFD-ED fed animals compared with HFD-corn oil. Moreover, increased nuclear protein levels of the Nfatc4 isoform strongly suggests up-regulation of slow-fiber-type gene expression in gSkM of HFD-ED fed animals compared with HFD-corn oil fed animals (Figure 4).


Eicosapentaenoic and Docosahexaenoic Acid-Enriched High Fat Diet Delays Skeletal Muscle Degradation in Mice
Schematic representation of the role of ED—enriched HFD on the gSkM transcriptome and modulation of ageing and/or obesity-induced sarcopenia in C57Bl/6J mice. Briefly, ED enriched HFD downregulates glucose synthase kinase 3 beta (Gsk3β) that phosphorylates nuclear factor of activated T cells (Nfatc4) and excludes it from entering into the nucleus. It also increases cytosolic calcium concentrations that in turn regulate calcineurin that then dephosphorylates Nfat allowing its localization in the nucleus. Upon localization, Nfat forms complex with myogenin (Myog) to turn on slow-fiber-type specific gene-program for e.g., Troponin C1. Pgc1α, a known master regulator of mitochondrial biogenesis was also seen upregulated by ED enriched HFD that could act upon multiple targets, one of which regulating dephosphorylation of Nfatc4 isoforms and its further nuclear localization.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037530&req=5

nutrients-08-00543-f004: Schematic representation of the role of ED—enriched HFD on the gSkM transcriptome and modulation of ageing and/or obesity-induced sarcopenia in C57Bl/6J mice. Briefly, ED enriched HFD downregulates glucose synthase kinase 3 beta (Gsk3β) that phosphorylates nuclear factor of activated T cells (Nfatc4) and excludes it from entering into the nucleus. It also increases cytosolic calcium concentrations that in turn regulate calcineurin that then dephosphorylates Nfat allowing its localization in the nucleus. Upon localization, Nfat forms complex with myogenin (Myog) to turn on slow-fiber-type specific gene-program for e.g., Troponin C1. Pgc1α, a known master regulator of mitochondrial biogenesis was also seen upregulated by ED enriched HFD that could act upon multiple targets, one of which regulating dephosphorylation of Nfatc4 isoforms and its further nuclear localization.
Mentions: In this study, we have shown that HFD-ED improves muscle metabolism and promotes a switch to slow-fiber type compared to HFD-corn oil. HFD-ED improves metabolism of fatty acids in gSkM by upregulating expression of genes coding for proteins involved in fatty acid β-oxidation, the Krebs cycle and oxidative phosphorylation. Lipid analysis shows that the HFD-ED fed animals had lower total fatty acid content compared to HFD-corn oil and control diet fed animals. Reduced ectopic fat accumulation in HFD-ED compared with HFD-corn oil fed animals suggests a physiological effect of EPA and DHA on muscle metabolic health. Higher expression of the genes involved in muscle contraction was found in gSkM of HFD-ED fed animals compared with HFD-corn oil fed animals. Western blot analysis showed reduced Acc protein levels in gSkM of HFD-ED fed animals compared with HFD-corn oil, confirming gene expression results. Acc is an inhibitor of fatty acid β-oxidation in mitochondria and the lower levels shows increase in mitochondrial fatty acid β-oxidation. In addition, increased Tnnc1 levels suggest increased muscle contraction in gSkM of HFD-ED fed animals compared with HFD-corn oil. Moreover, increased nuclear protein levels of the Nfatc4 isoform strongly suggests up-regulation of slow-fiber-type gene expression in gSkM of HFD-ED fed animals compared with HFD-corn oil fed animals (Figure 4).

View Article: PubMed Central - PubMed

ABSTRACT

Low-grade chronic inflammatory conditions such as ageing, obesity and related metabolic disorders are associated with deterioration of skeletal muscle (SkM). Human studies have shown that marine fatty acids influence SkM function, though the underlying mechanisms of action are unknown. As a model of diet-induced obesity, we fed C57BL/6J mice either a high fat diet (HFD) with purified marine fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (HFD-ED), a HFD with corn oil, or normal mouse chow for 8 weeks; and used transcriptomics to identify the molecular effects of EPA and DHA on SkM. Consumption of ED-enriched HFD modulated SkM metabolism through increased gene expression of mitochondrial β-oxidation and slow-fiber type genes compared with HFD-corn oil fed mice. Furthermore, HFD-ED intake increased nuclear localization of nuclear factor of activated T-cells (Nfatc4) protein, which controls fiber-type composition. This data suggests a role for EPA and DHA in mitigating some of the molecular responses due to a HFD in SkM. Overall, the results suggest that increased consumption of the marine fatty acids EPA and DHA may aid in the prevention of molecular processes that lead to muscle deterioration commonly associated with obesity-induced low-grade inflammation.

No MeSH data available.