Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans
Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Bo...
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| Format: | Article |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.951390/full |
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| author | Dominic Maschari Gunjan Saxena Timothy D. Law Erin Walsh Mason C. Campbell Leslie A Consitt Leslie A Consitt Leslie A Consitt |
| author_facet | Dominic Maschari Gunjan Saxena Timothy D. Law Erin Walsh Mason C. Campbell Leslie A Consitt Leslie A Consitt Leslie A Consitt |
| author_sort | Dominic Maschari |
| collection | DOAJ |
| description | Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m2) and fourteen obese (40.6 ± 1.4 kg/m2) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner (p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance. |
| first_indexed | 2024-12-10T18:02:03Z |
| format | Article |
| id | doaj.art-3565c4259b0a4c278c892e5c6c40aff2 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-10T18:02:03Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-3565c4259b0a4c278c892e5c6c40aff22022-12-22T01:38:44ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-08-011310.3389/fphys.2022.951390951390Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humansDominic Maschari0Gunjan Saxena1Timothy D. Law2Erin Walsh3Mason C. Campbell4Leslie A Consitt5Leslie A Consitt6Leslie A Consitt7College of Health Sciences and Professions, Ohio University, Athens, OH, United StatesDepartment of Biomedical Sciences, Ohio University, Athens, OH, United StatesOhio Musculoskeletal and Neurological Institute, Ohio University, Athens, OH, United StatesBiological Sciences Department, Ohio University, Athens, OH, United StatesBiological Sciences Department, Ohio University, Athens, OH, United StatesDepartment of Biomedical Sciences, Ohio University, Athens, OH, United StatesOhio Musculoskeletal and Neurological Institute, Ohio University, Athens, OH, United StatesDiabetes Institute, Ohio University, Athens, OH, United StatesElevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m2) and fourteen obese (40.6 ± 1.4 kg/m2) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner (p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance.https://www.frontiersin.org/articles/10.3389/fphys.2022.951390/fullskeletal musclepost-translation modificationinsulin sensitivitylactylationlactateobesity |
| spellingShingle | Dominic Maschari Gunjan Saxena Timothy D. Law Erin Walsh Mason C. Campbell Leslie A Consitt Leslie A Consitt Leslie A Consitt Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans Frontiers in Physiology skeletal muscle post-translation modification insulin sensitivity lactylation lactate obesity |
| title | Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans |
| title_full | Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans |
| title_fullStr | Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans |
| title_full_unstemmed | Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans |
| title_short | Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans |
| title_sort | lactate induced lactylation in skeletal muscle is associated with insulin resistance in humans |
| topic | skeletal muscle post-translation modification insulin sensitivity lactylation lactate obesity |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.951390/full |
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