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Summary: Non-canonical Wnt signaling activated by Wnt5a/Wnt11 is required for the second heart field development in mice. However, the pathophysiological role of non-canonical Wnt signaling in the adult heart has not been fully elucidated. Here we show that cardiomyocyte-specific Wnt5a knockout mice exhibit improved systolic function and reduced expression of mechanosensitive genes including Nppb when subjected to pressure overload. In cultured cardiomyocytes, Wnt5a knockdown reduced Nppb upregulation induced by cyclic cell stretch. Upstream analysis revealed that TEAD1, a transcription factor that acts with Hippo pathway co-activator YAP, was downregulated both in vitro and in vivo by Wnt5a knockdown/knockout. YAP nuclear translocation was induced by cell stretch and attenuated by Wnt5a knockdown. Wnt5a knockdown-induced Nppb downregulation during cell stretch was rescued by Hippo inhibition, and the rescue effect was canceled by knockdown of YAP. These results collectively suggest that Wnt5a-YAP signaling axis mediates mechanotransduction in cardiomyocytes and contributes to heart failure progression.

Fibroblast growth factor (FGF)23 is a bone-derived phosphotropic hormone that regulates phosphate and mineral homeostasis. Recent studies have provided evidence that a high plasma concentration of FGF23 is associated with cardiac disease, including left ventricular hypertrophy (LVH), heart failure, atrial fibrillation, and cardiac death. Experimental studies have shown that FGF23 activates fibroblast growth factor receptor 4 (FGFR4)/phospholipase Cγ/calcineurin/nuclear factor of activated T-cells signaling in cardiomyocytes and induces cardiac hypertrophy in rodents. Activation of FGFR4 by FGF23 normally requires the co-receptor α-klotho, and klotho-independent signaling occurs only under conditions characterized by extremely high FGF23 concentrations. Recent studies have demonstrated that FGF23 activates the renin-angiotensin-aldosterone system (RAAS) and induces LVH, at least in part as a result of lower vitamin D activation. Moreover, crosstalk between FGF23 and RAAS results in the induction of cardiac hypertrophy and fibrosis. In this review, we summarize the results of studies regarding the relationships between FGF23 and cardiac events, and describe the potential direct and indirect mechanisms whereby FGF23 induces LVH.

BackgroundPatients with chronic kidney disease (CKD) have a high risk of left ventricular hypertrophy (LVH). Fibroblast growth factor 23 (FGF23) and indoxyl sulfate (IS) are associated with LVH in patients with CKD, but the interactions between these molecules remain unknown. We investigated whether IS contributes to LVH associated with FGF23 in cultured cardiomyocytes and CKD mice.Methods and resultsIn cultured rat cardiac myoblast H9c2 cells incubated with IS, mRNA levels of the LVH markers atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain were significantly upregulated. Levels of mRNA of the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which regulates FGF23 O-glycosylation, and FGF23 were also upregulated in H9c2 cells. Intact FGF23 protein expression and fibroblast growth factor receptor 4 (FGFR4) phosphorylation were increased in cell lysates by IS administration. In C57BL/6J mice with heminephrectomy, IS promoted LVH, whereas the inhibition of FGFR4 significantly reduced heart weight and left ventricular wall thickness in IS-treated groups. While there was no significant difference in serum FGF23 concentrations, cardiac FGF23 protein expression was markedly increased in IS-injected mice. GALNT3, hypoxia-inducible factor 1 alpha, and FGF23 protein expression was induced in H9c2 cells by IS treatment and suppressed by the inhibition of Aryl hydrocarbon receptor which is the receptor for IS.ConclusionThis study suggests that IS increases FGF23 protein expression via an increase in GALNT3 and hypoxia-inducible factor 1 alpha expression, and activates FGF23-FGFR4 signaling in cardiomyocytes, leading to LVH.

This study aims to investigate the prevalence of sarcopenic obesity and factors influencing body composition in persons with spinal cord injury (SCI) in Japan. Adults with SCI aged ≥ 20 years who underwent whole-body dual-energy X-ray absorptiometry between 2016 and 2022 were retrospectively analyzed. Data from 97 patients were examined. The primary outcome was appendicular skeletal muscle mass (ASM). Multiple linear regression analysis was conducted to assess factors influencing the lean and adipose indices in persons with SCI. Sarcopenia, obesity, and sarcopenic obesity were prevalent in 76%, 85%, and 64% of patients, respectively. Multivariate linear regression analysis revealed that sex (β = 0.34, p < 0.001), lesion level (β = 0.25, p = 0.007), severity (β = 0.20, p = 0.043), and ability to walk (β = 0.29, p = 0.006) were independently associated with ASM. Sex (β = −0.63, p < 0.001) was independently associated with percent body fat. In conclusion, sarcopenia, obesity, and sarcopenic obesity were prevalent among patients with SCI in Japan. Female sex, tetraplegia, motor-complete injury, and inability to walk were risk factors for sarcopenia, whereas female sex was a risk factor for obesity in persons with SCI. A routine monitoring of body composition is necessary, especially among those with multiple risk factors, to identify individuals in need of preventive and therapeutic interventions.

It has been reported that weight gain at discharge compared with admission is associated with improved activities of daily living in convalescent rehabilitation (CR) patients with low body mass index. Here, we investigated whether weight maintenance or gain during the early phase of CR after stroke correlates with a better functional recovery in patients with a wide range of BMI values. We conducted this retrospective cohort study in a CR ward of our hospital and included adult stroke patients admitted to the ward from January 2014 to December 2018. After ~1 month of hospitalization, the patients were classified into weight loss and weight maintenance or gain (WMG) groups based on the Global Leadership Initiative on Malnutrition criteria for weight. We adopted the motor functional independence measure (FIM) gain as the primary outcome. The motor FIM gain tended to be greater in the WMG group but without statistical significance. However, multiple regression analysis showed that WMG was significantly and positively associated with motor FIM gain. In conclusion, weight maintenance or gain in patients during the early phase of CR after stroke may be considered as a predictor of their functional recovery, and nutritional management to prevent weight loss immediately after the start of rehabilitation would contribute to this.

Objective: To investigate the relationship between changes in nutritional status and the functional outcome of adult post-stroke patients hospitalized for rehabilitation. Design: A cross-sectional study. Subjects: Post-stroke patients (n = 134) who were admitted to a convalescent rehabilitation ward. Methods: On admission and discharge, the nutritional status of each subject was assessed using the “controlling nutritional status” system. Activities of daily living were assessed using the Functional Independence Measure (FIM). Patients were divided into 2 categories: (i) those whose nutritional status improved or remained normal during the rehabilitation; and (ii) all others. Results: The median age of patients was 65.5 years. Although there were no significant differences between the 2 categories in most characteristics, the FIM efficiency was significantly higher (0.230 in the improved category and 0.133 in the other; p