The initiation of heartbeat is an essential step in cardiogenesis in the heart primordium, but it remains unclear how intracellular metabolism responds to increased energy demands after heartbeat initiation. In this study, embryos in Wistar rats at embryonic day 10, at which heartbeat begins in rats, were divided into two groups by the heart primordium before and after heartbeat initiation and their metabolic characteristics were assessed. Metabolome analysis revealed that increased levels of ATP, a main product of glucose catabolism, and reduced glutathione, a by-product of the pentose phosphate pathway, were the major determinants in the heart primordium after heartbeat initiation. Glycolytic capacity and ATP synthesis-linked mitochondrial respiration were significantly increased, but subunits in complexes of mitochondrial oxidative phosphorylation were not upregulated in the heart primordium after heartbeat initiation. Hypoxia-inducible factor (HIF)-1α was activated and a glucose transporter and rate-limiting enzymes of the glycolytic and pentose phosphate pathways, which are HIF-1α-downstream targets, were upregulated in the heart primordium after heartbeat initiation. These results suggest that the HIF-1α-mediated enhancement of glycolysis with activation of the pentose phosphate pathway, potentially leading to antioxidant defense and nucleotide biosynthesis, covers the increased energy demand in the beating and developing heart primordium.
Interval training (IT) results in improved fatigue resistance in skeletal muscle mainly due to an increased aerobic capacity, which involves increased muscle mitochondrial content and/or improved mitochondrial function. We hypothesized that IT with high-intensity contractions is more effective in increasing mitochondrial function, and hence fatigue resistance, than low-intensity contractions. To study this hypothesis without interference from differences in muscle fiber recruitment obliged to occur during voluntary contractions, IT was performed with in situ supramaximal electrical stimulation where all muscle fibers are recruited.We compared the effect of IT with repeated low-intensity (20 Hz stimulation, IT20) and high-intensity (100 Hz stimulation, IT100) contractions on fatigue resistance and mitochondrial content and function in mouse plantar flexor muscles. Muscles were stimulated every other day for 4 weeks. The averaged peak torque during IT bouts was 4.2-fold higher with IT100 than with IT20. Both stimulation protocols markedly improved in situ fatigue resistance, although the improvement was larger with IT100. The citrate synthase activity, a biomarker of How to cite this article: Yamada T, Kimura I, Ashida Y, et al. Larger improvements in fatigue resistance and mitochondrial function with highthan with low-intensity contractions during interval training of mouse skeletal muscle. FASEB
Myofibrillogenesis is an essential process for cardiogenesis and is closely related to excitation-contraction coupling and the maintenance of heartbeat. It remains unclear whether the formation of myofibrils and sarcomeres is associated with heartbeat initiation in the early embryonic heart development. Here, we investigated the association between the ultrastructure of myofibrils assessed by transmission electron microscopy and their proteomic profiling assessed by data-independent acquisition mass spectrometry (DIA-MS) in the rat heart primordia before and after heartbeat initiation at embryonic day 10.0, when heartbeat begins in rats, and in the primitive heart tube at embryonic day 11.0. Bundles of myofilaments were scattered in a few cells of the heart primordium after heartbeat initiation, whereas there were no typical sarcomeres in the heart primordia both before and after heartbeat initiation. Sarcomeres with Z-lines were identified in cells of the primitive heart tube, though myofilaments were not aligned. DIA-MS proteome analysis revealed that only 43 proteins were significantly upregulated by more than 2.0 fold among a total of 7,762 detected proteins in the heart primordium after heartbeat initiation compared with that before heartbeat initiation. Indeed, of those upregulated proteins, 12 (27.9%) were constituent proteins of myofibrils and 10 (23.3%) were proteins that were accessories and regulators for myofibrillogenesis, suggesting that upregulated proteins that are associated with heartbeat initiation were enriched in myofibrillogenesis. Collectively, our results suggest that the establishment of heartbeat is induced by development of bundles of myofilaments with upregulated proteins associated with myofibrillogensis, whereas sarcomeres are not required for the initial heartbeat.
Quantitative data assessment on the basis of threedimensional gait analysis has been routinely used in the evaluation of pathological gait of children with cerebral palsy. However, a similar quantitative methodology has not been applied for spina bifida patients in whom atypical gait patterns are thought to correlate with various levels of neurological paralysis. The purpose of this study is to investigate the differences among gait patterns in spina bifida between different levels of neurological lesions using quantitative methods: Gait profile score (GPS) and gait variable scores (GVS), scoring subject's gait deviation from a reference. In this cross-sectional study, 22 children with spina bifida (11 women, 11 men; mean age 9.4 years, SD 3.8 years, range 3-17 years), were examined using three-dimensional gait analysis from 2008 to 2018. Physical examination allowed for classification of each of the 44 limbs as either L4, L5 or S1 and comparison with the GPS and GVS using a linear mixed model. GPS and the GVS of the pelvis and hip range of motion in the coronal plane were significantly higher in the L4 group than in the L5 and S1 groups (GPS, P = 0.041, P = 0.003, respectively; GVS of pelvis, P = 0.001, P = 0.001; GVS of hip, P < 0.001, P < 0.001) GVS (foot progression angle) was significantly lower in the S1 group than in L4 and L5 groups (P < 0.001, P = 0.037). We found that GPS and GVS enable us to quantitatively assess the differences among gait patterns between different neurological levels. The scoring tool showed the potential for detecting individual neurological changes.
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