ANAYT ULLA, Honomi Ogura, Mizanur Md Rahman, Saya Nakamura, Yuka Ichiba, Haruka Tsuda, Takayuki Uchida, Hiroyuki Kayaki, Yosuke Nishitani, Susumu Yoshino, Hiroshige Kuwahara, Toshiro Matsui and Takeshi Nikawa : Protective effects of 3-(4-hydroxy-3-methoxyphenyl) propionic acid against dexamethasone-induced muscle atrophy: modulation of associated genes and oxidative stress in female mice., Biochemistry and Biophysics Reports, 45, 102483, 2026.
(要約)
Muscle atrophy is a growing concern, particularly in older adults and people with sedentary lifestyles. Because treatment options are limited, extensive research is crucial to discover novel therapeutic agents. Thus, we investigated the effect of 3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) and its parent compound, 4-hydroxy-3-methoxycinnamic acid (HMCA), on dexamethasone (Dex)-induced muscle atrophy in C57BL/6J female mice. Dex injection (10 mg/kg body weight [BW] in mice for 10 consecutive days negatively affected body weight, gastrocnemius and tibialis anterior muscle mass, myofiber cross sectional area (CSA) and level of myosin heavy chain (MyHC) protein. Atrogin-1 and muscle ring finger protein-1, two major muscle atrophy-associated ubiquitin ligases, were significantly increased following Dex administration, along with their upstream regulators forkhead box O3a (FoxO3a) and Krüppel-like factor 15 (KLF15). Furthermore, Dex-induced oxidative stress by increasing malondialdehyde and advanced oxidation protein products in plasma and skeletal muscle. Intriguingly, HMPA and HMCA administration (50 mg/kg BW) for 21 days effectively prevented the attenuation of muscle mass, myofiber CSA and MyHC protein levels and suppressed ubiquitin ligase expression by ameliorating the upstream transcriptional factors FoxO3a and KLF15. Moreover, increased oxidative stress and oxidative stress-sensitive casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) ubiquitin ligase induced by Dex were effectively diminished by HMPA/HMCA administration. These observations suggest that HMPA and HMCA may be potential in vivo therapeutic agents that attenuate muscle atrophy by reversing atrophy-mimicking genes, oxidative stress, and related anomalies.
Tomoya Fukawa, Miho Takata, Kota Kishida, Kosuke Sugiura, Minori Suzuki, Haruka Tsuda, Iori Sakakibara, Takayuki Uchida, Mizanur Md Rahman, ANAYT ULLA, Koichi Sairyo, Takahiko Sato, Madoka Ikemoto-Uezumi, Akiyoshi Uezumi and Takeshi Nikawa : Critical role of mitochondrial aconitase in skeletal muscle maturation, Scientific Reports, 15, 1, 42957, 2025.
(要約)
Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.
Junsoo Park, ANAYT ULLA, Takayuki Uchida, Siyun Lee, Haruka Tsuda, Tomoko Ishige, Toko Hashizume, Akira Higashibata, Rackhyun Park, Takeshi Kobayashi, Masahiro Sokabe, Inho Choi and Takeshi Nikawa : Celastrol and Cblin peptide activation of IGF-1 signaling prevents microgravity-induced atrophy in rat L6 myotubes, American Journal of Physiology, Cell Physiology, 330, 1, C70-C82, 2025.
(要約)
This study investigated the efficacy of two natural compounds-celastrol, a heat shock protein (HSP) inducer, and Cblin peptide, a ubiquitination inhibitor-in counteracting muscle atrophy under real microgravity conditions. Both agents independently attenuated microgravity-induced reductions in myotube thickness, myosin heavy chain protein levels, and atrogene expression. Celastrol primarily enhanced HSP expression, whereas Cblin peptide inhibited insulin receptor substrate-1 degradation, thereby promoting insulin-like growth factor-1 signaling. Despite their distinct molecular actions, no synergistic or additive effects were observed when combined. These findings highlight the potential of celastrol and Cblin peptide as functional ingredients for mitigating muscle atrophy, particularly in the context of space travel. Notably, Cblin peptide is abundant in glycinin-rich soybean protein, and celastrol is derived from the root of Tripterygium wilfordii (Taiwan vine). Future applications may include incorporating these plant-derived compounds into space foods to improve the quality of life for astronauts in space.NEW & NOTEWORTHY This study evaluated the effects of celastrol and the Cblin peptide in mitigating muscle atrophy under microgravity conditions. Both compounds alleviated myotube atrophy through distinct mechanisms, though no synergistic effect was observed. Celastrol upregulated heat shock protein (HSP) expression, whereas Cblin prevented IRS-1 degradation, thereby enhancing IGF-1 signaling. Sourced from Tripterygium wilfordii and soybean protein, respectively, these agents may serve as functional space foods to help counteract muscle atrophy and support astronauts' health during spaceflight.
Haruka Tsuda, Takayuki Uchida, Saki Okuno, ANAYT ULLA, S Kawakami, S Mori, S Maruki-Uchida and Takeshi Nikawa : Piceatannol Enhances Intracellular Energy Metabolism via SIRT1 in C2C12 Cells, Advances in Biological Chemistry, 15, 54-69, 2025.
6.
ANAYT ULLA, Mizanur Md Rahman, Takayuki Uchida, Hiroyuki Kayaki, Yosuke Nishitani, Susumu Yoshino, Hiroshige Kuwahara and Takeshi Nikawa : 3-(4-Hydroxy-3-methoxyphenyl) propionic acid mitigates dexamethasone-induced muscle atrophy by attenuating Atrogin-1 and MuRF-1 expression in mouse C2C12 skeletal myotubes, Journal of Clinical Biochemistry and Nutrition, 76, 1, 16-24, 2025.
Mizanur Md Rahman, ANAYT ULLA, Hiroki Moriwaki, Yusuke Yasukawa, Takayuki Uchida and Takeshi Nikawa : Muscle-Protective Effect of Carnosine against Dexamethasone-Induced Muscle Atrophy in C2C12 Myotube., Journal of Nutritional Science and Vitaminology, 70, 3, 219-227, 2024.
(要約)
This study investigated the protective effect of carnosine and its components (L-histidine and β-alanine [HA]) against dexamethasone (Dex)-induced muscle atrophy in C2C12 myotubes. Myotubes were treated with Dex (10 μM) to induce muscle atrophy manifested by decreased myotube diameter, low myosin heavy chain content, and increased expression of muscle atrophy-associated ubiquitin ligases (Atrogin-1, MuRF-1, and Cbl-b). Carnosine (20 mM) treatment significantly improved the myotube diameter and MyHC protein expression level in Dex-treated C2C12 myotubes. It also downregulated the expression of Atrogin-1, MuRF-1, and Cbl-b and suppressed the expression of forkhead box O3 (FoxO3a) mediated by Dex. Furthermore, reactive oxygen species production was increased by Dex but was ameliorated by carnosine treatment. However, HA (20 mM), the component of carnosine, treatment was found ineffective in preventing Dex-induced protein damage. Therefore, based on above results it can be suggested that carnosine could be a potential therapeutic agent to prevent Dex-induced muscle atrophy compared to its components HA.
(キーワード)
Carnosine / Dexamethasone / Muscular Atrophy / Muscle Fibers, Skeletal / Animals / Mice / Muscle Proteins / Cell Line / Reactive Oxygen Species / SKP Cullin F-Box Protein Ligases / Ubiquitin-Protein Ligases / Forkhead Box Protein O3 / Tripartite Motif Proteins / Myosin Heavy Chains
Takayuki Uchida, Madoka Kohno, Chinami Itoh, Erika Yamano, Hiroki Matsuki, MIZANUR MD Rahman, ANAYT ULLA, Minori Suzuki, Takahiro Ishiguro and Takeshi Nikawa : Inhibitory Effect of Kori-tofu Protein on Denervation-Induced Atrogene Expression in Mouse Skeletal Muscle, Biological Sciences in Space, 38, 1-7, 2024.
(要約)
<p>Soy glycinin contains a functional inhibitory sequence, DIpYNP, against muscle-atrophy-associated ubiquitin ligase Cbl-b. It inhibited the binding of Cbl-b and IRS-1 (called Cblin-like peptide) and improved denervation-induced muscle atrophy in mice. In the present study, we evaluated the anti-muscle atrophy effect by feeding Kori-tofu to a mouse model of muscle atrophy induced by sciatic nerve transection, because Kori-tofu is a freeze-dried tofu made mainly from soy proteins. In the mice fed with Kori-tofu for one week, no significant inhibition in the reduction of the tibialis anterior (TA), gastrocnemius (GA) or soleus (SOL) muscle due to denervation was observed, compared with those of mice fed a soy protein isolate (SPI) or casein. However, in the TA muscle of the Kori-tofu-fed group, a significant suppression of the increased expression levels of muscle atrophy-related genes, MAFbx/atrogin-1 and MuRF-1, induced by denervation was observed similarly as that of mice fed a SPI. Additionally, the denervation-mediated decrease in the fast-twitch type myosin heavy chain (MyHC) level was suppressed in the TA of the Kori-tofu-fed group. Thus, our results suggest that Kori-tofu could be a useful and perishable functional space food against unloading-mediated muscle atrophy.</p>
ANAYT ULLA, Kanae Osaki, Mizanur Md Rahman, Reiko Nakao, Takayuki Uchida, Isafumi Maru, Kazuaki Mawatari, Tomoya Fukawa, Hiro-omi Kanayama, Iori Sakakibara, Katsuya Hirasaka and Takeshi Nikawa : Morin improves dexamethasone-induced muscle atrophy by modulating atrophy-related genes and oxidative stress in female mice., Bioscience, Biotechnology, and Biochemistry, 86, 10, 1448-1458, 2022.
(要約)
This study investigated the effect of morin, a flavonoid, on dexamethasone-induced muscle atrophy in C57BL/6J female mice. Dexamethasone (10 mg/kg body weight) for 10 days significantly reduced body weight, gastrocnemius and tibialis anterior muscle mass, and muscle protein in mice. Dexamethasone significantly upregulated muscle atrophy-associated ubiquitin ligases, including atrogin-1 and MuRF-1, and the upstream transcription factors FoxO3a and Klf15. Additionally, dexamethasone significantly induced the expression of oxidative stress-sensitive ubiquitin ligase Cbl-b and the accumulation of the oxidative stress markers malondialdehyde and advanced protein oxidation products in both the plasma and skeletal muscle samples. Intriguingly, morin treatment (20 mg/kg body weight) for 17 days effectively attenuated the loss of muscle mass and muscle protein and suppressed the expression of ubiquitin ligases while reducing the expression of upstream transcriptional factors. Therefore, morin might act as a potential therapeutic agent to attenuate muscle atrophy by modulating atrophy-inducing genes and preventing oxidative stress.
Madoka Kohno, ANAYT ULLA, Rina Taniguchi, Akane Ohishi, Kako Hirayama, Yuma Takemura, Shoichiro Takao, Yuki Kanazawa, Yuki Matsumoto, Masafumi Harada, Tomoya Fukawa, Hiro-omi Kanayama, Takayuki Uchida, Toshio Suzuki and Takeshi Nikawa : Daily Dietary Supplementation with Steamed Soybean Improves Muscle Volume and Strength in Healthy People Lacking Exercise., Journal of Nutritional Science and Vitaminology, 68, 6, 521-526, 2022.
(要約)
Various dietary protein supplements are used by the elderly and bedridden to maintain their skeletal muscle mass and functions. High-quality proteins act as an anabolic driver and help to improve muscle strength and performance. Previously, we reported that soy protein significantly attenuates denervation-induced loss of muscle mass and myofiber cross sectional area in mice with inhibition of ubiquitination and degradation of IRS-1 in tibialis anterior muscle. It also increased muscle volume and strength in bedridden patients. In the present study, we investigated the effects of dietary soybean supplementation on muscle functions in taxi drivers lacking vigorous physical exercise. We conducted a case-control study on 25 healthy, male taxi drivers between the ages of 36 and 71 y performing minimal physical exercise. They were divided into two dietary groups: the soybean diet group (n=13) who ate daily meals (dinner) supplemented with 50 g of steamed soybean for 30 d and the control diet group (n=12) who received no soybean supplement. Next, we measured the muscle cross-sectional area (CSA) and muscle strength and function in both the groups before and after 30 d of soybean intake. The body weights of both diet groups did not differ significantly over time. However, after 30 d of soybean supplementation, the soybean-fed group developed significantly higher muscle CSA and grip strength compared to the control groups. In conclusion, dietary soybean supplementation improved muscle function in taxi drivers who lacked exercise.
Takeshi Nikawa, ANAYT ULLA and Iori Sakakibara : Polyphenols and Their Effects on Muscle Atrophy and Muscle Health, Molecules, 26, 16, 4887, Aug. 2021.
(要約)
Skeletal muscle atrophy is the decrease in muscle mass and strength caused by reduced protein synthesis/accelerated protein degradation. Various conditions, such as denervation, disuse, aging, chronic diseases, heart disease, obstructive lung disease, diabetes, renal failure, AIDS, sepsis, cancer, and steroidal medications, can cause muscle atrophy. Mechanistically, inflammation, oxidative stress, and mitochondrial dysfunction are among the major contributors to muscle atrophy, by modulating signaling pathways that regulate muscle homeostasis. To prevent muscle catabolism and enhance muscle anabolism, several natural and synthetic compounds have been investigated. Recently, polyphenols (i.e., natural phytochemicals) have received extensive attention regarding their effect on muscle atrophy because of their potent antioxidant and anti-inflammatory properties. Numerous in vitro and in vivo studies have reported polyphenols as strongly effective bioactive molecules that attenuate muscle atrophy and enhance muscle health. This review describes polyphenols as promising bioactive molecules that impede muscle atrophy induced by various proatrophic factors. The effects of each class/subclass of polyphenolic compounds regarding protection against the muscle disorders induced by various pathological/physiological factors are summarized in tabular form and discussed. Although considerable variations in antiatrophic potencies and mechanisms were observed among structurally diverse polyphenolic compounds, they are vital factors to be considered in muscle atrophy prevention strategies.
Potential biofunction of mulberry polyphenols as energy regulator via mitochondrial-associated ER membrane (MAM) in skeletal muscle (研究課題/領域番号: 23K19925 )