SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis

脊髄性筋萎縮症における骨格筋病変の発症メカニズムの一部を解明. 京都大学プレスリリース. 2023-01-17.Pathogenesis of skeletal muscle lesions in spinal muscular atrophy. 京都大学プレスリリース. 2023-02-17.Spinal muscular atrophy (SMA) is a congenital neuromuscular disease caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although the primary cause of progressive muscle atrophy in SMA has classically been considered the degeneration of motor neurons, recent studies have indicated a skeletal muscle–specific pathological phenotype such as impaired mitochondrial function and enhanced cell death. Here, we found that the down-regulation of SMN causes mitochondrial dysfunction and subsequent cell death in in vitro models of skeletal myogenesis with both a murine C2C12 cell line and human induced pluripotent stem cells. During myogenesis, SMN binds to the upstream genomic regions of MYOD1 and microRNA (miR)-1 and miR-206. Accordingly, the loss of SMN down-regulates these miRs, whereas supplementation of the miRs recovers the mitochondrial function, cell survival, and myotube formation of SMN-deficient C2C12, indicating the SMN-miR axis is essential for myogenic metabolic maturation. In addition, the introduction of the miRs into ex vivo muscle stem cells derived from Δ7-SMA mice caused myotube formation and muscle contraction. In conclusion, our data revealed novel transcriptional roles of SMN during myogenesis, providing an alternative muscle-oriented therapeutic strategy for SMA patients

Long-term Monitoring of the Black Hole Binary GX 339-4 in the High/Soft State during the 2010 Outburst with MAXI/GSC

We present the results of monitoring the Galactic black hole candidate GX 339-4 with the Monitor of All-sky X-ray Image (MAXI) / Gas Slit Camera (GSC) in the high/soft state during the outburst in 2010. All the spectra throughout the 8-month period are well reproduced with a model consisting of multi-color disk (MCD) emission and its Comptonization component, whose fraction is <= 25% in the total flux. In spite of the flux variability over a factor of 3, the innermost disk radius is constant at R_in = 61 +/- 2 km for the inclination angle of i = 46 deg and the distance of d=8 kpc. This R_in value is consistent with those of the past measurements with Tenma in the high/soft state. Assuming that the disk extends to the innermost stable circular orbit of a non-spinning black hole, we estimate the black hole mass to be M = 6.8 +/- 0.2 M_sun for i = 46 deg and d = 8 kpc, which is consistent with that estimated from the Suzaku observation of the previous low/hard state. Further combined with the mass function, we obtain the mass constraint of 4.3 M_sun < M < 13.3 M_sun for the allowed range of d = 6-15 kpc and i < 60 deg. We also discuss the spin parameter of the black hole in GX 339-4 by applying relativistic accretion disk models to the Swift/XRT data.Comment: 9 pages, 8 figures, accepted for publication in PASJ (Suzaku+MAXI special issue

A Large X-ray Flare from a Single Weak-lined T Tauri Star TWA-7 Detected with MAXI GSC

We present a large X-ray flare from a nearby weak-lined T Tauri star TWA-7 detected with the Gas Slit Camera (GSC) on the Monitor of All-sky X-ray Image (MAXI). The GSC captured X-ray flaring from TWA-7 with a flux of $3\times10^{-9}$ ergs cm$^{-2}$ s$^{-1}$ in 2--20 keV band during the scan transit starting at UT 2010-09-07 18:24:30.The estimated X-ray luminosity at the scan in the energy band is 3$\times10^{32}$ ergs s$^{-1}$,indicating that the event is among the largest X-ray flares fromT Tauri stars.Since MAXI GSC monitors a target only during a scan transit of about a minute per 92 min orbital cycle, the luminosity at the flare peak might have been higher than that detected. At the scan transit, we observed a high X-ray-to-bolometric luminosity ratio, log $L_{\rm X}/L_{\rm bol}$ = $-0.1^{+0.2}_{-0.3}$; i.e., the X-ray luminosity is comparable to the bolometric luminosity. Since TWA-7 has neither an accreting disk nor a binary companion, the observed event implies that none of those are essential to generate such big flares in T Tauri stars.Comment: 4 pages, 2 figures, 1 table accepted for publication in PAS

Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.

Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.We thank Kaori Yoshida, Keiko Uchiyama, Satomi Kawai, Naomi Hatanaka, Yoko Sawaguchi, Runa Washio, Takako Ichihashi, Nanako Koike, Keiko Uchiyama, Masaaki Nameta (Niigata University), Kaori Igarashi, Kaori Saitoh, Keiko Endo, Hiroko Maki, Ayano Ueno, Maki Ohishi, Sanae Yamanaka, Noriko Kagata (Keio University) for their excellent technical assistance, C. Ronald Kahn (Joslin Diabetes Center and Harvard Medical School) for providing the BAT cell line, Evan Rosen (Harvard Medical School) for providing us Ucp-Cre mice, Kosuke Morikawa (Kyoto University), Tomitake Tsukihara (University of Hyogo) and Shinya Yoshikawa (University of Hyogo) for their professional opinions and suggestions. Tis work was supported by a Grant-in-Aid for Scientifc Research (A) (20H00533) from MEXT, AMED under Grant Numbers JP20ek0210114, and AMED-CREST under Grant Number JP20gm1110012, and Moonshot Research and Development Program (21zf0127003s0201), MEXT Supported Program for the Strategic Research Foundation at Private Universities Japan, Private University Research Branding Project, and Leading Initiative for Excellent Young Researchers, and grants from the Takeda Medical Research Foundation, the Vehicle Racing Commemorative Foundation, Ono Medical Research Foundation, and the Suzuken Memorial Foundation (to T.M.). Support was also provided by a Grants-in-Aid for Young Scientists (Start-up) (26893080), and grants from the Uehara Memorial Foundation, Kowa Life Science Foundation, Manpei Suzuki Diabetes Foundation, SENSHIN Medical Research Foundation, ONO Medical Research Foundation, Tsukada Grant for Niigata University Medical Research, Te Nakajima Foundation, SUZUKEN memorial foundation, HOKUTO Corporation, Mochida Memorial Foundation for Medical & Pharmaceutical Research, Grants-in-Aid for Encouragement of Young Scientists (A) (16H06244), Daiichi Sankyo Foundation of Life Science, AMED Project for Elucidating and Controlling Mechanisms of Aging and Longevity under Grant Number JP17gm5010002, JP18gm5010002, JP19gm5010002, JP20gm5010002, JP21gm5010002, Astellas Foundation for Research on Metabolic Disorders, Research grant from Naito Foundation, Te Japan Geriatrics Society (to I.S.); by a Grant-in-Aid for Scientifc Research (C) (19K08974), Yujin Memorial Grant, Sakakibara Memorial Research Grant from Te Japan Research Promotion Society for Cardiovascular Diseases, TERUMO Life Science Foundation, Kanae Foundation (to Y.Y.), JST ERATO (JPMJER1902), AMED-CREST (JP20gm1010009), the Takeda Science Foundation, the Food Science Institute Foundation (to S.F.), and by a grant from Bourbon (to T.M., I.S. and Y.Y.).S

Sedentary Time and All-Cause Mortality

BACKGROUND: This study aimed to determine the association between sedentary time and mortality with regard to leisure‐time physical activity with or without cardiometabolic diseases such as hypertension, dyslipidemia, and diabetes mellitus. METHODS AND RESULTS: Using data from the J‐MICC (Japan Multi‐Institutional Collaborative Cohort) Study, 64 456 participants (29 022 men, 35 434 women) were analyzed. Hazard ratios (HRs) and 95% CIs were used to characterize the relative risk of all‐cause mortality to evaluate its association with sedentary time (categorical variables: <5, 5 to <7, 7 to <9, ≥9 h/d and 2‐hour increments in exposure) according to the self‐reported hypertension, dyslipidemia, and diabetes mellitus using a Cox proportional hazards model. A total of 2257 participants died during 7.7 years of follow‐up. The corresponding HRs for each 2‐hour increment in sedentary time among participants with all factors, no factors, hypertension, dyslipidemia, and diabetes mellitus were 1.153 (95% CI, 1.114–1.194), 1.125 (95% CI, 1.074–1.179), 1.202 (95% CI, 1.129–1.279), 1.176 (95% CI, 1.087–1.273), and 1.272 (95% CI, 1.159–1.396), respectively. Furthermore, when analyzed according to the combined different factors (hypertension, dyslipidemia, and diabetes mellitus), HRs increased with each additional factor, and participants reporting all 3 conditions had the highest HR of 1.417 (95% CI, 1.162–1.728) independently of leisure‐time metabolic equivalents. CONCLUSIONS: The association between sedentary time and increased mortality is stronger among patients with hypertension, dyslipidemia, and diabetes mellitus regardless of leisure‐time physical activity in a large Japanese population

Peculiarly Narrow SED of GRB 090926B with MAXI and Fermi/GBM

The monitor of all-sky X-ray image (MAXI) Gas Slit Camera (GSC) on the International Space Station (ISS) detected a gamma-ray burst (GRB) on 2009, September 26, GRB\,090926B. This GRB had extremely hard spectra in the X-ray energy range. Joint spectral fitting with the Gamma-ray Burst Monitor on the Fermi Gamma-ray Space Telescope shows that this burst has peculiarly narrow spectral energy distribution and is represented by Comptonized blackbody model. This spectrum can be interpreted as photospheric emission from the low baryon-load GRB fireball. Calculating the parameter of fireball, we found the size of the base of the flow $r_0 = (4.3 \pm 0.9) \times 10^{9} \, Y^{\prime \, -3/2}$ cm and Lorentz factor of the plasma $\Gamma = (110 \pm 10) \, Y^{\prime \, 1/4}$, where $Y^{\prime}$ is a ratio between the total fireball energy and the energy in the blackbody component of the gamma-ray emission. This $r_0$ is factor of a few larger, and the Lorentz factor of 110 is smaller by also factor of a few than other bursts that have blackbody components in the spectra.Comment: 7 pages, 6 figure