Introduction: High intensity interval training (HIIT) has shown to be as effective as moderate intensity endurance training to improve metabolic health. However, the current knowledge on the effect of HIIT in older individuals is limited and it is uncertain whether the adaptations are sex specific. The aim was to investigate effects of HIIT on mitochondrial respiratory capacity and mitochondrial content in older females and males. Methods: Twenty‐two older sedentary males (n = 11) and females (n = 11) completed 6 weeks of supervised HIIT 3 days per week. The training consisted of 5 × 1 min cycling (124 ± 3% of max power output at session 2–6 and 135 ± 3% of max power output at session 7–20) interspersed by 1½ min recovery. Before the intervention and 72 h after last training session a muscle biopsy was obtained and mitochondrial respiratory capacity, citrate synthase activity and proteins involved in mitochondria metabolism were assessed. Furthermore, body composition and ⩒O₂max were measured. Results: ⩒O₂max increased and body fat percentage decreased after HIIT in both sexes (p < 0.05). In addition, CS activity and protein content of MnSOD and complex I‐V increased in both sexes. Coupled and uncoupled mitochondrial respiratory capacity increased only in males. Mitochondrial respiratory capacity normalised to CS activity (intrinsic mitochondrial respiratory capacity) did not change following HIIT. Conclusion: HIIT induces favourable adaptions in skeletal muscle in older subjects by increasing mitochondrial content, which may help to maintain muscle oxidative capacity and slow down the process of sarcopenia associated with ageing.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2 , a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c ^+/− fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c ^−/− larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes¹. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

Aerobic training can improve vascular endothelial function in-vivo. The aim of this study was to elucidate the mechanisms underlying this improvement in isolated human microvascular endothelial cells. Sedentary males, aged 57 ± 6 years completed 8 weeks of intense aerobic training. Resting muscle biopsies were obtained from the thigh muscle and used for isolation of endothelial cells (pre n = 23, post n = 16). The cells were analyzed for mitochondrial respiration, H₂O₂ emission, glycolysis, protein levels of antioxidants, NADPH oxidase, endothelial nitric oxide (NO) synthase and prostacyclin synthase (PGI₂S). In-vivo microvascular function, assessed by acetylcholine infusion and arterial blood pressure were also determined. Endothelial mitochondrial respiration and H₂O₂ formation were similar before and after training whereas the expression of superoxide dismutase and the expression of glutathione peroxidase were 2.4-fold (p = 0.012) and 2.3-fold (p = 0.006) higher, respectively, after training. In-vivo microvascular function was increased by 1.4-fold (p = 0.036) in parallel with a 2.1-fold increase in endothelial PGI₂S expression (p = 0.041). Endothelial cell glycolysis was reduced after training, as indicated by a 65% lower basal production of lactate (p = 0.003) and a 30% lower expression of phosphofructokinase (p = 0.011). Subdivision of the participants according to blood pressure at base-line (n = 23), revealed a 2-fold higher (p = 0.049) rate of H₂O₂ production in endothelial cells from hypertensive participants. Our data show that exercise training increases skeletal muscle microvascular endothelial cell metabolism, antioxidant capacity and the capacity to form prostacyclin. Moreover, elevated blood pressure is associated with increased endothelial mitochondrial ROS formation.

The present study examined and compared the impact of exercise training on redox and molecular properties of human microvascular endothelial cells derived from skeletal muscle biopsies from sedentary recent (RPF, ≤ 5 years as postmenopausal) and late (LPF, ≥ 10 years as postmenopausal) postmenopausal females. Resting skeletal muscle biopsies were obtained before and after 8 weeks of intense aerobic exercise training for isolation of microvascular endothelial cells and determination of skeletal muscle angiogenic proteins and capillarisation. The microvascular endothelial cells were analysed for mitochondrial respiration and production of reactive oxygen species (ROS), glycolysis and proteins related to vascular function, redox balance and oestrogen receptors. Exercise training led to a reduced endothelial cell ROS formation (∼50%; P = 0.009 and P = 0.020 for intact and permeabilized cells (state 3), respectively) in RPF only, with no effect on endothelial mitochondrial capacity in either group. Basal endothelial cell lactate formation was higher (7%; P = 0.028), indicating increased glycolysis, after compared to before the exercise training period in RPF only. Baseline endothelial G protein‐coupled oestrogen receptor (P = 0.028) and muscle capillarisation (P = 0.028) was lower in LPF than in RPF. Muscle vascular endothelial growth factor protein was higher (32%; P = 0.002) following exercise training in LPF only. Exercise training did not influence endothelial cell proliferation or skeletal muscle capillarisation in either group, but the CD31 level in the muscle tissue, indicating endothelial cell content, was higher (>50%; P < 0.05) in both groups. In conclusion, 8 weeks of intense aerobic exercise training reduces ROS formation and enhances glycolysis in microvascular endothelial cells from RPF but does not induce skeletal muscle angiogenesis. image Key points: Late postmenopausal females have been reported to achieve limited vascular adaptations to exercise training. There is a paucity of data on the effect of exercise training on isolated skeletal muscle microvascular endothelial cells (MMECs). In this study the formation of reactive oxygen species in MMECs was reduced and glycolysis increased after 8 weeks of aerobic exercise training in recent but not late postmenopausal females. Late postmenopausal females had lower levels of G protein‐coupled oestrogen receptor in MMECs and lower skeletal muscle capillary density at baseline. Eight weeks of intense exercise training altered MMEC properties but did not induce skeletal muscle angiogenesis in postmenopausal females.