Physiological adaptations of stroke patients after high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) remain unclear. This study determined the HIIT and MICT effects on aerobic capacity, cerebral oxygenation, peak cardiac output (CO), and serum brain-derived neurotrophic factor (BDNF) in stroke patients. We included 23 stroke patients with age about 55 years and stroke duration>24 months; participants completed 36 sessions of exercise training for 30min; 13 were randomly assigned to perform MICT at 60% of peak oxygen consumption (VO2peak) and 10 to perform HIIT at alternating 80% (3min) and 40% (3min) VO2peak. Before and after interventions, we evaluated VO2peak, peak CO, arteriovenous oxygen difference (AV O2diff), bilateral frontal cortex oxygenation (relative changes of oxyhemoglobin Δ[O2Hb], deoxyhemoglobin Δ[HHb], and total hemoglobin Δ[THb] levels), serum brain-derived neurotrophic factor (BDNF) level, and fluorescent cell staining for neuron morphology and percentage of cell-bearing neurites (% neurites). HIIT induced significant increases in VO2peak (P=0.008), CO (P=0.038), Δ[HHb] (P=0.046), Δ[THb] (P=0.046), and serum BDNF level (P=0.012). The improvement in VO2peak was significantly greater with HIIT than MICT (20.7% vs. 9.8%, P=0.031), as was AV O2diff (P=0.041), Δ[HHb] (P=0.027), and serum BDNF level (P<0.001). HIIT facilitated neuron dendritic protrusions (greater % neurites, P=0.012) with prominent redistribution of mitochondria. As compared with MICT, HIIT-improved aerobic capacity by increasing systemic tissue O2 extraction in stroke patients. Increased cerebral O2 utilization in the involved hemisphere was also identified after HIIT. These physiological adaptations may be associated with increased serum BDNF level. In vitro dendritic growth in neurons treated with serum from HIIT participants may imply significant effects on neuron activities as compared with MICT. CLINICALTRIALS. NCT04135391.

N-cadherin is a trans-membrane adhesion molecule associated with advanced carcinoma progression and poor prognosis. The effect of N-cadherin on matrix metalloproteinase 9 (MMP-9) regulation is implicated in human nasopharyngeal carcinoma (NPC) cell invasion. Exposure of NPC cells to phorbol-12-myristate-13-acetate (PMA) or macrophage conditioned media (CM) upregulated MMP-9 and N-cadherin cleavage, which resulted in NPC cell invasion. MMP-9 cleaved the extracellular domain of N-cadherin, which was further cleaved by γ-secretase with PMA or macrophage-CM treatment. The extracellular cleavage of N-cadherin was inhibited with treatment with an MMP inhibitor and MMP-9 siRNA, whereas the intracellular cleavage of N-cadherin was inhibited by treatment with a γ-secretase inhibitor (γI), which resulted in enhanced accumulation of N-cadherin C-terminal fragment (CTF1, ~40 kDa). CTF2/N-cad (CTF2), a product of the γ-secretase cleavage of N-cadherin, was released and translocated into the nuclear compartment in PMA-treated cells. Moreover, CTF2 enhanced the effect of PMA-mediated MMP-9 gene expression as assessed by treatment with γI or overexpression with exogenous CTF2. Additionally, siRNA silencing of N-cadherin decreased PMA-mediated MMP-9 expression and cell invasion. The outside-in signaling effect of MMP-9 in macrophage CM- or PMA-treated cell cultures significantly enhanced NPC cell invasion via N-cadherin cleavage. Extracellular and intracellular cleavage of N-cadherin might be involved in elevated MMP-9 expression enhancing tumor cell invasion. Furthermore, N-cadherin–affected tumor progression might be via enhanced MMP-9 signaling in a cross-talk regulatory mechanism. N-cadherin might contribute to the invasive characteristics of carcinoma cells by upregulating MMP-9, thereby leading to increased aggressive metastasis.

Exercise training (ET) may impact physical fitness by affecting mitochondrial functions. This study aimed to elucidate the effect of ET on aerobic capacity and platelet mitochondrial bioenergetics (MTB) in stroke patients. Among the 30 stroke patients who underwent the traditional rehabilitation program (TRP), 15 were randomly assigned to have ET (50–60% VO_2peak for 30 min/day, 5 days/week for 4 weeks), and those remaining received only the TRP (control group). The peak exercise capacity (VO_2peak) and platelet MTB, including oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC), were measured through automatic gas analysis and high-resolution respirometry, respectively. The results demonstrated that ET significantly increased the VO_2peak (17.7%) and O₂ uptake efficiency slope (31.9%) but decreased the ventilation versus CO₂ production slope (−7.65%). Patients who underwent ET also had significantly enhanced platelet mitochondrial OXPHOS and ETC by activating the FADH2 (Complex II)-dependent pathway, but depressed plasma myeloperoxidase (−28.4%) and interleukin-6 levels (−29.9%). Moreover, changes in VO_2peak levels were positively correlated with changes in platelet OXPHOS and ETC capacities. In conclusion, ET increases the platelet MTB by enhancing Complex II activity in stroke patients. The exercise regimen also enhances aerobic fitness and depresses oxidative stress/pro-inflammatory status in stroke patients.

This matched-control cohort study explored the effects of high-intensity interval training (HIIT) on left ventricle (LV) dimensions and survival in heart failure (HF) patients between 2009 and 2016. HF patients who underwent the multidisciplinary disease management program (MDP) were enrolled. Non-exercising participants, aged (mean (95% confidence interval)) 62.8 (60.1–65.5) years, were categorized as the MDP group (n = 101). Participants aged 61.5 (58.7–64.2) years who had completed 36 sessions of HIIT were treated as the HIIT group (n = 101). Peak oxygen consumption (VO_2peak) and LV geometry were assessed during the 8-year follow-up period. The 5-year all-cause mortality risk factors and overall survival rates were determined in the longitudinal observation. An increased VO_2peak of 14–20% was observed in the HIIT group after exercise training. Each 1-mL/kg/min increase in VO_2peak conferred a 58% improvement in 5-year mortality. Increased LV end-systolic diameter (LVESD) was significantly (p = 0.0198) associated with increased mortality. The 8-month survival rate was significantly improved (p = 0.044) in HIIT participants compared to non-exercise participants. HF patients with VO_2peak ≥14.0 mL/kg/min and LVESD <44 mm had a significantly better 5-year survival rate (98.2%) than those (57.3%) with lower VO_2peak and greater LVESD. Both HIIT-induced increased VO_2peak and decreased LVESD are associated with improved survival in HF patients.

Exercise training influences the risk of vascular thrombosis in patients with peripheral arterial disease (PAD). Mitochondrial functionalities in platelets involve the cellular bioenergetics and thrombogenesis. This study aimed to elucidate the effect of cycling exercise training (CET) on platelet mitochondrial bioenergetics in PAD patients. Forty randomly selected patients with PAD engaged in general rehabilitation (GR) with CET (i.e., cycling exercise at ventilation threshold for 30 minute/day, 3 days/week) (GR + CET, n = 20) or to a control group that only received GR course (n = 20) for 12 weeks. Systemic aerobic capacity and platelet mitochondrial bioenergetics that included oxidative phosphorylation (OXPHOS) and electron transport system (ETS) were measured using automatic gas analysis and high-resolution respirometry, respectively. The experimental results demonstrated that GR + CET for 12 weeks significantly (1) elevated VO_2peak and lowered V_E-VCO₂ slope, (2) raised resting ankle-brachial index and enhanced cardiac output response to exercise, (3) increased the distance in 6-minute walk test and raised the Short Form-36 physical/mental component scores, and (4) enhanced capacities of mitochondrial OXPHOS and ETS in platelets by activating FADH2 (complex II)-dependent pathway. Moreover, changes in VO_2peak levels were positively associated with changes in platelet OXPHOS and ETS capacities. However, no significant changes in systemic aerobic capacity, platelet mitochondrial bioenergetics, and health-related quality of life (HRQoL) occurred following GR alone. Hence, we conclude that CET effectively increases the capacities of platelet mitochondrial bioenergetics by enhancing complex II activity in patients with PAD. Moreover, the exercise regimen also enhanced functional exercise capacity, consequently improving HRQoL in PAD patients. J.-S.W., T.-C.F., and C.-C.H. were involved in conception and design of research; M.-L.L., T.-C.F., S.-C.H., and Y.-T.L. performed experiments; J.-S.W., T.-C.F., and M.-L.L. analyzed data, interpreted results of experiments, prepared the figures, and drafted the paper; J.-S.W. and T.-C.F. edited and revised the paper; J.-S.W., M.-L.L., T.-C.F., C.-C.H., S.-C.H., and Y.-T.L. approved the final version of the paper. ^* Equal contribution as the first author. Received: 05 August 2020 Accepted: 17 November 2020 Publication Date: 09 January 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany