Christopher L Axelrod1, Ciaran E Fealy2, Melissa L Erickson3, Gangarao Davuluri4, Hisashi Fujioka5, Wagner S Dantas6, Emily Huang2, Kathryn Pergola7, Jacob T Mey3, William T King7, Anny Mulya2, Daniel Hsia8, Bartolome Burguera9, Bernard Tandler10, Charles L Hoppel11, John P Kirwan12. 1. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 2. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 3. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 4. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Sarcopenia and Malnutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. 5. Cryo-Electron Microscopy Core, Case Western Reserve University, Cleveland, OH 44109, USA; Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. 6. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. 7. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. 8. Clinical Trials Unit, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. 9. Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. 10. Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH 44106, USA. 11. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44109, USA. 12. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: john.kirwan@pbrc.edu.
Abstract
BACKGROUND AND AIMS: A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS: 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS: Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS: These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCT02697201, ClinicalTrials.gov.
BACKGROUND AND AIMS: A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS: 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS: Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS: These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCT02697201, ClinicalTrials.gov.
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