Aerobic function and skeletal muscle plasticity in health and disease

[摘要] In recent decades, chronic diseases have reached epidemic proportions in the industrialised world. A physically inactive lifestyle has been identified as a major factorcausing maladaptations leading to coronary heart disease, stroke, hypertension, type 2 diabetes, osteoporosis, breast cancer, and colon cancer. Regular physical activityprevents the development of obesity and induces a multitude of favourable adaptations within skeletal muscle and the cardio-respiratory system, which have positiveoutcomes for both the prevention and treatment of metabolic diseases. Specifically, high aerobic function is related to physical activity whereas low aerobic function isrelated to physical inactivity and various metabolic diseases. In order to gain a better understanding of the mechanisms underlying aerobic function and skeletal muscleplasticity it is fundamental to identify which specific exercise stimuli leads to what molecular response, and how this molecular response relates to the structural, contractile, and metabolic adaptation. Thus, the present thesis was aimed at providing new insights into the mechanisms underlying aerobic function and skeletal muscleplasticity by using an integrative approach including cell culture, rodent, and human models.In a first study, in order to shed light upon the relationship of aerobic function and type 1 diabetes, we investigated factors that may limit oxidative capacity and aerobic exercise performance in young untrained women with type 1 diabetes. Calf muscle oxidative capacity was not different between untrained women with type 1 diabetesand healthy women of similar age and activity levels. Notably, HbA1c was negatively correlated with mitochondrial capacity in women with type 1 diabetes. AlthoughHbA1c was negatively correlated with cardiac output in women with type 1 diabetes, maximal oxygen consumption, cardiac output, endurance capacity, skeletal muscleoxidative enzyme activity, and capillary-to-fibre ratio were not reduced in women with type 1 diabetes compared to healthy women. These results indicate that oxidativecapacity depends on HbA1c in untrained women with type 1 diabetes but aerobic function is not reduced relative to untrained healthy women. Thus, it is important toaccurately control glycaemic status in future studies investigating the aerobic function in patients with type 1 diabetes.In a second study, we aimed at establishing a cell culture model to closely recapitulate the plastic changes in gene expression as observed in aerobically trained skeletalmuscles of mice. In electrically stimulated C2C12 mouse muscle cells the transcriptional adaptations were almost identical to those in endurance trained skeletal musclesof mice, but differed from the acute effects of exercise on muscle gene expression.In addition, significant alterations in the expression of myofibrillar proteins indicated that this in vitro exercise model could be used to modulate the fibre-typeof muscle cells in culture. Our data thus describe an experimental cell culture model for the study of at least some of the transcriptional aspects of skeletal muscle adaptation to physical activity.Typically, aerobic function can be improved by repeated endurance exercise but not by resistance exercise. To overcome the specificity of this adaptive response weaimed in a third study at designing a new resistance exercise model with superimposed stimuli to induce endurance type adaptations and to test its effectiveness inhumans. Indeed, 5 weeks of whole-body vibration training with superimposed heavy resistance exercise and sustained vascular occlusion (VRO) increased capillary-tofibreratio, skeletal muscle oxidative enzyme activity, myosin heavy chain type 1 fibre proportion, and endurance capacity. In a fourth study, we analysed the molecularbases underlying these adaptations. A single bout of VRO increased the expression of vascular endothelial growth factor (VEGF) mRNA through reactive oxygen species(ROS)-activated peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) probably in a hypoxia-inducible factor 1α (HIF-1α) independent manner. In conclusion,modified high-intensity resistance exercise activates gene programmes typically linked to endurance exercise.

[发布机构] University of Zurich

[效力级别] Center for Integrative Human Physiology

[关键词] Institute of Physiology;Center for Integrative Human Physiology;570 Life sciences;biology;610 Medicine & health