Lipidstoffwechsel im humanen Skelettmuskel in Bezug zu Insulinsensitivität - Einfluss von körperlicher Aktivität und Fettsäuren
Zusammenfassung der Projektergebnisse
A sedentary lifestyle combined with increased consumption of high energy food plays a pivotal role in development of obesity, a major risk factor to develop type 2 diabetes. On the other side, regular exercise training effectively prevents the development of obesity, insulin resistance and type 2 diabetes. To investigate mechanisms underlying the health-beneficial effects of exercise training the human exercise intervention study MyoGlu was used as a platform. In this study twenty-six middle-aged, sedentary men underwent combined endurance and strength training for 12 weeks resulting among others in improved insulin sensitivity. Skeletal muscle biopsies and blood samples were taken before and after an acute bicycle test, performed at baseline as well as after 12 weeks of training intervention. mRNA sequencing was used as an untargeted approach to study gene expression of stearoyl-CoA desaturase (SCD), perilipins, mitogen-activated protein kinase phosphatases (MKPs) and secreted proteins in skeletal muscle upon acute as well as long-term exercise. SCD was found to be an exercise-responsive gene with higher expression after long-term exercise thus supporting existing literature data. Comparing the effect of acute endurance vs. resistance exercise we found hints pointing to a potential role of SCD in exercise-related hypertrophic adaptation of skeletal muscle. However, this finding requires further evaluation. Among all five perilipins expressed in skeletal muscle PLIN4 exhibited the highest expression, and its expression was significantly reduced after long-term exercise. Interestingly, we found PLIN4 mainly localized on subsarcolemmal lipid droplets in muscle fibers, with higher levels in slow-twitch as compared to fast-twitch skeletal muscle fibers. The two ERK1/2-specific MKPs, dual specificity phosphatase 5 (DUSP5) and DUSP6, were the most regulated MKPs in skeletal muscle after acute exercise. In vitro experiments using human myotubes revealed that stimulation of ERK1/2 activity was required for induction of DUSP5. We suggest that the altered expression of DUSP5 and DUSP6 in skeletal muscle after acute endurance exercise might affect ERK1/2 signaling, which is of importance for adaptations in skeletal muscle during exercise. Finally, we identified transcripts encoding secretory proteins that were changed more than 1.5-fold in muscle after exercise. In total, we found 161 candidate secretory transcripts that were up-regulated after acute exercise and 99 that where increased after 12 weeks exercise training. Furthermore, 92 secretory transcripts were decreased after acute and/or long-term physical activity. 17 of these transcripts were selected and further validated as novel myokines. One of the candidates we identified was macrophage colony-stimulating factor-1 (CSF1), which influences macrophage homeostasis. CSF1 mRNA expression increased in skeletal muscle after acute and long-term exercise, which was accompanied by a rise in circulating CSF1 protein. The results of this project verify that exercise training influences the gene expression of a wide range of targets and has comprehensive effects on skeletal muscle. We identified some novel players as exercise-responsive, which may play key roles in local and systemic adaptations to exercise, including improved insulin sensitivity.
Projektbezogene Publikationen (Auswahl)
- (2015): Perilipin 4 in human skeletal muscle: localization and effect of physical activity. Physiol Rep, 3(8). pii: e12481
Pourteymour S, Lee S, Langleite TM, Eckardt K, Hjorth M, Bindesbøll C, Dalen KT, Birkeland KI, Drevon CA, Holen T, Norheim F
(Siehe online unter https://dx.doi.org/10.14814/phy2.12481) - (2015): The effect of acute and long-term physical activity on extracellular matrix and serglycin in human skeletal muscle. Physiol Rep, 3(8). pii: e12473
Hjorth M, Norheim F, Meen AJ, Pourteymour S, Lee S, Holen T, Jensen J, Birkeland KI, Martinov VN, Langleite TM, Eckardt K, Drevon CA, Kolset SO
(Siehe online unter https://dx.doi.org/10.14814/phy2.12473) - (2016): Electrical Pulse Stimulation of Cultured Skeletal Muscle Cells as a Model for in vitro Exercise – Possibilities and Limitations. Acta Physiol, 220(3):310-331
Nikolic N, Görgens SW, Thoresen GH, Aas V, Eckel F, Eckardt K
(Siehe online unter https://doi.org/10.1111/apha.12830) - (2017): Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise, Physiol Rep, 5(19). pii: e13459
Pourteymour S, Hjorth M, Lee S, Holen T, Langleite TM, Jensen J, Birkeland KI, Drevon CA, Eckardt K
(Siehe online unter https://doi.org/10.14814/phy2.13459) - (2017): Global mRNA sequencing of human skeletal muscle: search for novel exercise-regulated myokines. Mol Metab, 6(4):352-365
Pourteymour S, Eckardt K, Holen T, Langleite TM, Lee S, Jensen J, Birkeland KI, Drevon CA, Hjorth M
(Siehe online unter https://doi.org/10.1016/j.molmet.2017.01.007)
