Exercise-Induced Mitochondrial Biogenesis Involving Insulin Sensitivity, Associated with Type 2 Diabetes Mellitus
Introduction. Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both1. Insulin resistance corresponds with a failure of pancreatic islets to compensate for the decline in insulin sensitivity (β-cell failure) associated with impaired mitochondrial respiration and augmented oxidative stress1,2. Recent studies have found that exercise induces mitochondrial dynamics and glucose tolerance/utilization in tissue-specific and systemic settings, suggesting potential prevention and treatment mechanisms for T2DM3-5. Methods. Mice were randomly assigned to the sedentary or exercise group without or with a running wheel, respectively. Western blotting evaluated mitochondrial protein levels in mice skeletal muscle and subcutaneous white adipose tissue (scWAT). scWAT from donor trained mice was transplanted to sedentary recipient mice. Fiber-type-specific proteomics analysis probed human skeletal muscle biopsies before and after 12 weeks of endurance training. Single fibers were typified using MHC antibodies. A 75-g oral glucose tolerance test (OGTT) measured levels of incretin hormones, including glucagon-like polypeptide-1 (GLP-1). Results. The levels of various mitochondrial proteins involved in glucose utilization, including glycolysis, glycogen metabolism, pyruvate dehydrogenase complex, tricarboxylic acid cycle, and oxidative phosphorylation, increased after exercise in skeletal muscle in human whole-muscle samples4. These mitochondrial proteins also elevated in skeletal muscle and white adipose tissue in comparison to sedentary mice5. Iron sulfur domain-containing (CISD) proteins, mitochondrial matrix proteins that upregulate mitochondrial biogenesis, had amplified expression after exercise in mice skeletal muscle and scWAT5. Furthermore, the association between CISD and mitochondrial protein expression in the plantaris muscle and WAT in mice was positively correlated5. Transient decreases in blood glucose were observed in mice transplanted with scWAT from trained mice 9 days after transplantation6. Additionally, GLP-1, a metabolic hormone that diminishes blood glucose levels by augmenting insulin secretion, increased in the blood coupled with the decline in blood glucose levels after exercise training. Conclusions. The positive association between CISD proteins and mitochondrial dynamics proposes exercise directly maintains mitochondrial integrity to prevent the progression of T2DM-mediated oxidative stress and failure of oxidative phosphorylation. The elevation of mitochondrial proteins indicates a potential mechanism for bolstered mitochondrial involvement in glucose uptake/utilization after exercise, associated with potential preventions and treatments for T2DM. The short-term improvements in glucose tolerance evince significant endocrine effects on systemic metabolism after exercise. The exercise-induced change in the blood suggests GLP-1 and other incretins may be some of the signals involved with exercise and its effects to reduce blood glucose levels, critical for evaluation of risk and treatments for T2DM.
- Goyal R, Jialal I. Diabetes Mellitus Type 2. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 20, 2020.
- Javeed N, Matveyenko AV. Circadian Etiology of Type 2 Diabetes Mellitus. Physiology (Bethesda). 2018;33(2):138-150. doi:10.1152/physiol.00003.2018
- Tanaka Y, Ogata H, Kayaba M, et al. Effect of a single bout of exercise on clock gene expression in human leukocyte. J Appl Physiol (1985). 2020;128(4):847-854. doi:10.1152/japplphysiol.00891.2019
- Deshmukh AS, Steenberg DE, Hostrup M, Birk JB, Larsen JK, Santos A, Kjøbsted R, Hingst JR, Schéele CC, Murgia M, Kiens B, Richter EA, Mann M, Wojtaszewski JFP. Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training. Nat Commun. 2021 Jan 12;12(1):304. doi: 10.1038/s41467-020-20556-8. Erratum in: Nat Commun. 2021 Mar 5;12(1):1600. PMID: 33436631; PMCID: PMC7803955.
- Yokokawa T, Kido K, Suga T, et al. Exercise training increases CISD family protein expression in murine skeletal muscle and white adipose tissue. Biochem Biophys Res Commun. 2018;506(3):571-577. doi:10.1016/j.bbrc.2018.10.101Kujala UM. Is physical activity a cause of longevity? It is not as straightforward as some would believe. A critical analysis. Br J Sports Med. 2018;52(14):914-918. doi:10.1136/bjsports-2017-098639
- Stanford KI, Middelbeek RJ, Goodyear LJ. Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations [published correction appears in Diabetes. 2015 Sep;64(9):3334]. Diabetes. 2015;64(7):2361-2368. doi:10.2337/db15-0227
- Malin SK, Francois ME, Eichner NZM, et al. Impact of short-term exercise training intensity on β-cell function in older obese adults with prediabetes. J Appl Physiol (1985). 2018;125(6):1979-1986. doi:10.1152/japplphysiol.00680.2018