Search

Pharmacologic β-blockade is a well-established therapy for reducing adverse effects from sympathetic overactivity in cardiovascular diseases, such as heart failure. Despite decades of research efforts, in vivo cardiac functional studies using genetic animal models remain scant. We generated a mouse model of cardiomyocyte-specific deletion (cKO) of β-1 adrenergic receptor (ADRB1), the primary subtype expressed in cardiac myocytes, and demonstrated the role of ADRB1 in the maintenance of cardiac function at baseline and during exposure to increase in cardiac afterload by transient aortic occlusion and increasing heart rates (HRs) via atrial pacing. cKO hearts showed mildly depressed baseline left ventricular (LV) function, including slower HR, decreased contractility (dP/dt max/IP), and prolonged relaxation (Tau) in both sexes. Exposure to increased LV afterload depressed LV function in either genotype similarly; however, the functional recovery following the removal of the afterload was severely impaired in cKO hearts, whereas cardiac function was immediately normalized in wild-type (WT) hearts. When HR was altered from 400 to 700 beats/min, cKO hearts were deficient in HR-dependent improvement of cardiac contractility and relaxation, known as positive force-frequency relationship, that was evident in WT hearts. Enhanced phosphorylation of phospholamban by the HR increase was markedly blunted in cKO myocardium versus wild types, whereas CaMKII phosphorylation was comparable between the genotypes, suggesting the critical involvement of PKA. These results provide the first experimental evidence for the role of ADRB1 in cardiomyocytes for maintaining cardiac function at baseline and during acute stress, providing a clinical perspective relating to the management of patients on β-blockers. NEW & NOTEWORTHY Although the benefits of β-1 adrenergic receptor (ADRB1) blockade to cardiovascular disease are established, in vivo role for cardiomyocyte ADRB1 remains undetermined. Generating cardiomyocyte-specific ADRB1 knockout mice, we show that ADRB1 is pivotal to cardiac functional recovery from afterload elevation and heart rate-dependent functional enhancement as well as baseline performance. Our findings highlight the importance of cardiomyocyte ADRB1 in cardiac stress adaptability, which is of clinical importance in the management of patients on β-blockers.

Runx2 is an essential transcription factor for osteoblast differentiation and chondrocyte maturation. The spatiotemporal expression of Runx2 is regulated by enhancers. We previously identified a 1.3 kb osteoblast-specific enhancer; however, mice with this deletion showed no phenotypes. A 0.8 kb conserved region detected near the 1.3 kb enhancer did not exhibit enhancer activity in reporter assays, whereas four tandem repeats of 452 bp (452 × 4) containing the most conserved region of 0.8 kb induced strong reporter activity in chondrocyte cell lines. However, chondrocytes of enhanced green fluorescent protein (EGFP) reporter mice using 452 × 4 did not express EGFP. When 452 × 4 was combined with the 1.3 kb enhancer, hypertrophic chondrocytes highly expressed EGFP. Moreover, the 0.8 kb region combined with the 1.3 kb enhancer induced EGFP expression in prehypertrophic and hypertrophic chondrocytes. The deletion of both the 1.3 kb enhancer and the 0.8 kb conserved region slightly reduced Runx2 expression in the limbs. However, neither homozygous nor heterozygous deletions in the Runx2 +/- background showed phenotypes. The 0.8 kb conserved region itself lacked enhancer activity, but when combined with the 1.3 kb enhancer, EGFP expression was induced in chondrocytes with a similar expression pattern to Runx2. Therefore, the 0.8 kb conserved region has a novel function as a subenhancer.

Aim: Injury to and laxity of the pelvic floor muscles are highly important factors in the etiology of pelvic organ prolapse. When women with pelvic organ prolapse perform the Valsalva maneuver, progressive descent and widening of the levator ani muscle are observed on dynamic magnetic resonance images. However, physical examination of such women often reveals pelvic floor laxity, even in a relaxed state. Therefore, we aimed to verify the hypothesis that sagging of the pelvic floor can be detected on resting-state magnetic resonance images in the supine position., Methods: We retrospectively evaluated resting-state magnetic resonance imaging findings in women with (n = 193; all underwent surgical treatment) and without (controls; n = 193) pelvic organ prolapse who had at least one prior vaginal delivery. We compared the lengths of the pubococcygeal line, H-line, and M-line between the groups., Results: The median lengths (interquartile ranges) for the prolapse and control groups were 98.3 (91.9-104.0) and 95.1 (90.3-101.4) mm (p = 0.0011), respectively, for the pubococcygeal line; 61.5 (56.0-67.9) and 51.1 (47.2-55.6) mm (p < 0.0001), respectively, for the H-line; and 24.6 (20.4-29.0) and 8.6 (3.9-13.0) mm (p < 0.0001), respectively, for the M-line. Similarly, in the multiple regression analysis adjusted for age, height, body mass index, a history of operative vaginal delivery, and a history of hysterectomy, the pubococcygeal line, H-line, and M-line were significantly longer in the prolapse group., Conclusions: In women with pelvic organ prolapse, the H-line and M-line are significantly longer on resting-state magnetic resonance images, allowing for the detection of pelvic floor relaxation., (© 2025 Japan Society of Obstetrics and Gynecology.)

Sonic Hedgehog (Shh), encoding an extracellular signaling molecule, is vital for heart development. Shh null mutants show congenital heart disease due to left-right asymmetry defects stemming from functional anomaly in the midline structure in mice. Shh signaling is also known to affect cardiomyocyte differentiation, endocardium development, and heart morphogenesis, particularly in second heart field (SHF) cardiac progenitor cells that contribute to the right ventricle, outflow tract, and parts of the atrium. Despite extensive studies, our understanding remains incomplete. Notably, Shh signaling is suggested to promote cardiac differentiation, while paradoxically preventing premature differentiation of SHF progenitors. In this study, we elucidate the role of Shh signaling in the earliest phase of cardiac differentiation. Our meta-analysis of single-cell RNA sequencing suggests that cardiogenic nascent mesoderm cells expressing the bHLH transcription factor Mesp1 interact with axial mesoderm via Hh signaling. Activation of Hh signaling using a Smoothened agonist delayed or suppressed the differentiation of primitive streak cells expressing T-box transcription factor T to Mesp1 + nascent mesoderm cells both in vitro and ex vivo. Conversely, inhibition of Hh signaling by cyclopamine facilitated cardiac differentiation. The reduction of Eomes, an inducer of Mesp1, by Hh signaling appears to be the underlying mechanism of this phenomenon. Our data suggest that SHH secreted from axial mesoderm inhibits premature differentiation of T + cells to Mesp1 + nascent mesoderm cells, thereby regulating the pace of cardiac differentiation. These findings enhance our comprehension of Shh signaling in cardiac development, underscoring its crucial role in early cardiac differentiation., (© 2025 The Author(s). Development, Growth & Differentiation published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Developmental Biologists.)

Aim: Despite the clinical importance and significant social burden of neuropsychiatric symptoms (NPS) in dementia, the underlying neurobiological mechanism remains poorly understood. Recently, neuroimaging-derived brain-age estimation by machine-learning analysis has shown promise as an individual-level biomarker. We investigated the relationship between NPS and brain-age in amnestic mild cognitive impairment (MCI) and early dementia., Methods: In this cross-sectional study, clinical data, including neuropsychiatric inventory (NPI), and structural brain MRI of 499 individuals with clinical diagnoses of amnestic MCI (n = 185), early Alzheimer's disease (AD) (n = 258) or dementia with Lewy bodies (DLB) (n = 56) were analyzed. We established a brain-age prediction model using 694 healthy brain MRIs and a support vector regression model and applied it to the participants' data. Finally, the brain-predicted age difference (brain-PAD: predicted age minus chronological age) was calculated., Results: All groups showed significantly increased brain-PAD, and the median (IQR) brain-PAD was 4.3 (5.4) years in MCI, 6.3 (6.2) years in AD, and 5.0 (6.5) years in DLB. The NPI scores were subdivided into the following four categories: (i) Agitation and Irritability, (ii) Depression and Apathy, (iii) Delusions and Hallucinations, and (iv) Euphoria and Disinhibition. We found a significantly positive correlation between brain-PAD and the depression/apathy factor (Spearman's rs = 0.156, FDR-corrected P = 0.002), whereas no significance was shown for the other NPS factors., Conclusion: Higher brain-age may be associated with depression and apathy symptoms presented in MCI to early dementia stages, and brain-age analysis may be useful as a novel biomarker for the assessment or monitoring of NPS., (© 2025 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR + ) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR + neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA A receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR + neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.