Fumiko Shinkai-Ouchi, Yoshiki Itoh, Mayumi Shindo, Kyohei Mikami, Yoshinobu Iguchi, Shoji Hata, Rie Tsutsumi, Yuna Izumi, Kyoka Machida, Yuki Suzuki, Hiroshi Sakaue and Yasuko Ono : Distinct systemic metabolic features in limb-girdle muscular dystrophy type R1 mouse models as a potential early pathogenic signature, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1871, 7, 167983, 2025.
(要約)
Limb-girdle muscular dystrophy type R1 (LGMDR1, formerly LGMD2A) is a genetic disorder caused by mutations in CAPN3 and is characterized by progressive proximal limb muscle weakness. The CAPN3 gene product, calpain-3/CAPN3/p94, is a member of the intracellular cysteine protease superfamily predominantly expressed in the skeletal muscle. LGMDR1 pathogenesis has been investigated separately using mouse models: CAPN3:C129S [knock-in (KI)] mice, which express a proteolytically inactive variant, and CAPN3 knockout (KO) mice. These studies propose that CAPN3 bears both proteolytic activity-dependent and -independent functions and that the loss of either or both affects phenotypes. Here, we report a side-by-side, long-term analysis of KI and KO mice to comprehensively understand the LGMDR1 pathology in terms of CAPN3 function. Their physiques were comparable to those of wild-type animals, but age-dependent LGMDR1 symptoms were observed by histochemical analysis, with more severe symptoms observed in KO mice. Quantitative muscle proteomics and gene ontology analyses revealed more diverse changes in the KO mice than in the KI mice. Of the associated terms, "metabolic process" was the most affected across the genotype and age groups. Metabolomic analysis suggested that the skeletal muscles of these mice had an imbalance in the branched-chain amino acid catabolic pathway. Furthermore, a reduction in lipids and glycogen was observed in the liver of KO mice, suggesting that a systemic energy deficit occurs during CAPN3 deficiency. Altogether, our results suggest that muscular dysfunction in LGMDR1 models is associated with compromised systemic energy balance and that the extent of perturbation is implicated in disease severity.
Masashi Kuroda, Kazuhiro Nomura, Rin Chamoto, Yuna Izumi, Sonoko Yasui-Yamada, M. Yasuo Tsutsumi, Rie Tsutsumi and Hiroshi Sakaue : DNA methyltransferase inhibition by 5-azacytidine promotes thermogenic programming in beige adipocytes, Biochemical and Biophysical Research Communications, 774, 152094, 2025.
(要約)
Beige adipocytes play a critical role in energy metabolism by promoting thermogenesis, a process largely influenced by epigenetic modifications such as DNA methylation. This study investigates the effect of DNA demethylation on beige adipocyte differentiation and function using 5-azacytidine (5-AzaC), a DNA methyltransferase inhibitor. We evaluated changes in adipogenic and thermogenic gene expression, mitochondrial activity, and fatty acid uptake following 5-AzaC treatment in 3T3-L1-derived beige adipocytes. Our findings indicate that 5-AzaC does not significantly affect adipocyte differentiation but enhances thermogenic gene expression, including Ucp1 and Cox7a1, and increases mitochondrial function and fatty acid uptake. These results suggest that DNA demethylation modulates beige adipocyte function and may have implications for metabolic disorders such as obesity and type 2 diabetes.
Sonoko Yasui-Yamada, Teruhiro Morishita, Umemoto Nobuhiko, Rie Tsutsumi, Kohno Kazuyo, Shiota Shunsuke, Shinohara Mina, Yuna Izumi, Kazuhiro Nomura, Hiroshi Sakaue and Eiji Takeda : Daily Energy and Protein Intake Requirements to Prevent Body Weight Loss in Elderly Residents of Nursing Homes, Curēus, 17, 5, e83983, 2025.
4.
Momoko Kyomen, Ayako Tatsumi, Rie Tsutsumi, Yuna Izumi, Mizusa Hyodo, Eiji Tanaka, Kohta Iguchi, Kojiro Taura, Hiroaki Terajima, Sachiko Honjo, Akihiro Hamasaki, Kazuhiro Nomura and Hiroshi Sakaue : Urinary Titin on the First Postoperative Day Predicts Long-Term Skeletal Muscle Loss in Patients with Gastroenterological Cancer, International Journal of Molecular Sciences, 26, 5, 2025.
(要約)
Perioperative malnutrition is common in patients with gastroenterological cancer and contributes to postoperative skeletal muscle atrophy, which adversely affects their prognosis. Early assessment of skeletal muscle atrophy is crucial for improving postoperative outcomes. This study aimed to evaluate the efficacy of urinary titin as a biomarker for skeletal muscle atrophy. A prospective observational study was conducted, and a total of 34 gastroenterological cancer patients were included. Urinary titin levels were measured using ELISA at admission, postoperative days (POD) 1, 7, and 14, and at 6 months after surgery. Surgical procedure, operative time, cancer stage, postoperative complications, hospital stay, and preoperative and postoperative body composition were evaluated, along with nutritional status and grip strength from admission to 6 months after surgery. Changes in urinary titin levels were measured at the same time points as described above. Preoperatively, the mean urinary titin level was 5.03 pmol/mg Cr, slightly higher than in healthy subjects. Urinary titin peaked at 33.71 (24.30-66.58) pmol/mg/dL Cr on POD1 and was associated with serum free branched-chain amino acid concentrations. Urinary titin on POD1 was significantly correlated with a decrease in skeletal muscle mass (rs -0.361, p = 0.036) and body cell mass (rs -0.361, p = 0.038) at 6 months postoperatively. The grip strength at 6 months postoperatively tended to decrease (rs -0.342, p = 0.052). BMI and serum LDH at admission were associated with urinary titin on POD1 but were not correlated with skeletal muscle loss at 6 months, suggesting that urinary titin on POD1 is an independent biomarker of skeletal muscle atrophy. These data indicate that urinary titin on POD1 can predict long-term skeletal muscle atrophy.
(キーワード)
gastroenterological cancer / skeletal muscle atrophy / urinary titin
Kazuhiro Nomura, Yuki Yamasaki, Kana Takeji, Sachie Deha, Kaho Yamashita, Yuna Izumi, Sonoko Yasui-Yamada, Masashi Kuroda, Nagakatsu Harada, Tadahiro Kitamura, M. Yasuo Tsutsumi, Rie Tsutsumi, Yutaka Nakaya and Hiroshi Sakaue : Gut-pancreas axis in the control of insulin secretion in streptozotocin-resistant rats, Biochemical and Biophysical Research Communications, 752, 151487, 2025.
(要約)
The Spontaneously Running Tokushima Shikoku (SPORTS) rat is characterized by hyperactive behavior but is also a potential model for studies of the role of the gut-pancreas axis in the regulation of insulin secretion. We here explored the role of ghrelin, a hormone associated with appetite regulation, in insulin dynamics within the context of streptozotocin (STZ) resistance in SPORTS rats. Comprehensive analyses-including histological examinations, gene expression profiling, and assessment of metabolic parameters-revealed that SPORTS rats are resistant to STZ-induced pancreatic injury and that, in addition to low circulating ghrelin levels, they manifest increased circulating levels of active glucagon-like peptide-1 (GLP-1) and upregulated expression of Pdx1 in the pancreas. Ghrelin administration attenuated the STZ resistance of these rats, with suppression of GLP-1 and downregulation of Pdx1 expression being implicated in this effect. Our results highlight the complex interplay among ghrelin, GLP-1, and insulin dynamics, and they suggest potential new therapeutic targets for diabetes.
Mizusa Hyodo, Kazuhiro Nomura, Rie Tsutsumi, Yuna Izumi, Hibiki Kawaguchi, Ayuka Kawakami, Kanako Hara, Yuki Suzuki, Taku Shirakawa, Kayo Osawa, Masafumi Matsuo and Hiroshi Sakaue : Urinary titin as an early biomarker of skeletal muscle proteolysis and atrophy in various catabolic conditions, Biochemical and Biophysical Research Communications, 737, 150918, 2024.
(要約)
Skeletal muscle atrophy impairs quality of life and increases the risk of disease, but current methods for assessment of muscle mass have several limitations. We here investigated the urinary concentration of a fragment of the muscle protein titin as a potential biomarker for the early detection of skeletal muscle atrophy. Four mouse models with different atrophy pathways were studied: those of cardiotoxin-induced acute muscle injury, cast-induced muscle immobilization, lipopolysaccharide-induced sepsis, and streptozotocin-induced diabetes. In all four models, urinary titin levels increased early, concurrent with or preceding upregulation of the atrophy-related genes for atrogin-1 and MuRF-1. The increase in the urinary titin concentration was thus associated with initial muscle damage and the onset of proteolysis, rather than with late-stage muscle wasting. Our findings suggest that urinary titin is a promising biomarker for detection of the onset of skeletal muscle catabolism and prediction of the subsequent development of atrophy in different catabolic states. Noninvasive measurement of urinary titin may therefore allow the earlier detection of skeletal muscle proteolysis compared with conventional techniques.
Hiromi Matsuo, Ryota Matsui, Koshi Kumagai, Satoshi Ida, Yoko Saino, Aya Fujihara, Kumi Takagi, Yukiko Itami, Misuzu Ishii, Naoki Moriya, Yuna Izumi, Kazuhiro Nomura, M. Yasuo Tsutsumi, Souya Nunobe, Rie Tsutsumi and Hiroshi Sakaue : Impact of Olfactory Change on Postoperative Body Weight Loss in Patients with Gastric Cancer after Gastrectomy, Nutrients, 16, 6, 2024.
(要約)
Patients undergoing gastrectomy for gastric cancer may experience alterations in olfaction, yet the association between olfactory changes and postoperative weight loss remains uncertain. This study aimed to elucidate the relationship between olfactory changes and postoperative weight loss in patients with gastric cancer. Patients who underwent radical gastrectomy for gastric cancer between February 2022 and August 2022 were included in the study. Those experiencing a higher Visual Analog Scale (VAS) score postoperatively compared to preoperatively were deemed to have undergone olfactory changes. Postoperative weight loss was determined using the 75th percentile as a cutoff value, designating patients surpassing this threshold as experiencing significant weight loss. Multivariate logistic regression analysis was employed to identify risk factors for postoperative weight loss, with statistical significance set at p < 0.05. Out of 58 patients, 10 (17.2%) exhibited olfactory changes. The rate of postoperative weight loss at one month was markedly higher in the group with olfactory changes compared to those without (9.6% versus 6.2%, respectively; p = 0.002). In addition, the group experiencing olfactory changes demonstrated significantly lower energy intake compared to the group without such changes (1050 kcal versus 1250 kcal, respectively; p = 0.029). Logistic regression analysis revealed olfactory changes as an independent risk factor for significant weight loss at one month postoperatively (odds ratio: 7.64, 95% confidence interval: 1.09-71.85, p = 0.048). In conclusion, olfactory changes emerged as an independent risk factor for postoperative weight loss at one month in patients with gastric cancer following gastrectomy.
(キーワード)
body weight loss / gastrectomy / gastric cancer / olfaction / smell
Takahiro Kato, Satoshi Kamiya, Soshi Narasaki, Ayako Sumii, M Yasuo Tsutsumi, Kyoka Machida, Kanako Hara, Yuna Izumi, Rie Tsutsumi and Hiroshi Sakaue : Partially Hydrolyzed Guar Gum Intake Supports the Gut Microbiota and Attenuates Inflammation during Influenza H1N1 Virus Infection in Mice., Nutrients, 15, 19, 4252, 2023.
(要約)
Partially hydrolyzed guar gum (PHGG) is a soluble dietary fiber that is effective for defecation control. It influences the gut microbiota, by which it is metabolized to yield short-chain fatty acids (SCFAs), and it was also recently shown to protect against influenza infection in humans. We here investigated the effects of PHGG in a mouse model of influenza H1N1 virus infection. Eight-week-old C57BL/6 mice were fed normal chow with or without PHGG (500 mg/kg per day) for 4 weeks, infected with H1N1 at 10 weeks of age, and analyzed at 12 weeks of age. Administration of PHGG attenuated the decline in body weight induced by H1N1 infection without affecting food intake. It also ameliorated intestinal atrophy and increased the production of SCFAs including acetic acid, propionic acid, and butyric acid in the cecum, thereby preventing the inhibitory effect of H1N1 infection on SCFA production. The H1N1-induced increases in the serum concentrations of inflammatory cytokines including interferon-γ and interleukin-6 and anti-inflammatory cytokine such as interleukin-10 were all inhibited by PHGG intake. In addition, PHGG administration attenuated inflammatory gene expression in the lung and promoted both natural killer cell activity and regulatory T-cell differentiation in the spleen. Our findings suggest that the consumption of PHGG may improve the gut environment and thereby limit the inflammatory response to H1N1 infection. They may thus provide the basis for novel dietary intervention strategies to suppress the excessive inflammation associated with virus infection.
Hiromi Matsuo, Ryota Matsui, Koshi Kumagai, Satoshi Ida, Yoko Saino, Aya Fujiwara, Kumi Takagi, Yukiko Itami, Misuzu Ishii, Naoki Moriya, Yuna Izumi, Kazuhiro Nomura, M. Yasuo Tsutsumi, Souya Nunobe, Rie Tsutsumi and Hiroshi Sakaue : Reply to Lee, S.Y. Comment on ``Matsuo et al. Impact of Olfactory Change on Postoperative Body Weight Loss in Patients with Gastric Cancer after Gastrectomy. Nutrients 2024, 16, 851'', Nutrients, 16, 15, 2024.
M Sugiuchi, Yuna Izumi, M Tsutsumi, T Shiuchi, Y Okamatsu, T Yoneshiro, Sonoko Yasui-Yamada, R Tsutsumi, Kazuhiro Nomura and H Sakaue : Regulatory mechanism of skeletal muscle-derived IL-6 expression: Impact on skeletal muscle-brown adipose tissue amino acid metabolism., Joint Conference of The 22nd Annual Meeting of Asian and Oceanian Myology Center and The 10th Annual Meeting of Japan Muscle Society., Sep. 2024.
2.
H Murakami, Yuna Izumi, E Oya, Sonoko Yasui-Yamada, R Tsutsumi, Kazuhiro Nomura and H Sakaue : The impact of ketogenic diets blended with medium-chain triacylglycerols on skeletal muscle metabolism during atrophy., Joint Conference of The 22nd Annual Meeting of Asian and Oceanian Myology Center and The 10th Annual Meeting of Japan Muscle Society., Sep. 2024.
3.
Kazuhiro Nomura, Y Hirata, Yuna Izumi, Sonoko Yasui-Yamada, A Krook, JR Zierath, Hiroshi Sakaue and W Ogawa : Adrenaline Resistance in Obese Skeletal Muscle Impairs Exercise Metabolism, Joint Conference of The 22nd Annual Meeting of Asian and Oceanian Myology Center and The 10th Annual Meeting of Japan Muscle Society, Sep. 2024.