Disuse muscle atrophy and bone destruction are caused by the lack of locomotive activity both in space and on Earth. Mechanical loading by exercise is effective in preventing disuse diseases and maintaining the musculoskeletal system. This review provides an overview of the changes in the musculoskeletal system of mice under varying gravitational conditions to quantitatively analyze these phenomena. The experiments performed that mice maintained normal gravity (1G) and hypergravity (2G) using a centrifugal device on Earth, as well as microgravity (µG) and artificial 1G gravity (AG) using a centrifugal device on the International Space Station (ISS Kibo). We investigated the effects of hypergravity and microgravity environments on the musculoskeletal tissues under conditions of active movement. The sequential studies revealed that exercise under both hypergravity and microgravity conditions has correlated positive and negative effects on the maintaining quality of the musculoskeletal system, suggesting that exercise with appropriate gravitational loading on active movement positively regulates the musculoskeletal system. Recently, it has become evident that disuse diseases of the musculoskeletal system, which are an active movement in the skeletal legs and occlusal jaw, cause various chain reactions not only to the locomotive system but also to the sensory organs, and brain nerves, showing the importance of preventing dementia through appropriate exercise loading. This review outlines the latest findings on mechanical control of the motor system aimed at preventing disuse diseases caused by inactivity due to aging and immobility, a concern that is expected to increase with the advent of a super-aged society.

Duchenne muscular dystrophy (DMD) is the most common and severe type of muscular dystrophy and is an intractable X-linked genetic disorder characterized by progressive muscle atrophy and weakness including skeletal, cardiac, and respiratory muscles. DMD is caused by disruption of the reading frame with mutations of the dystrophin gene (DMD) and the loss of dystrophin protein. Approximately 1 in 5,000 boys are diagnosed with DMD. Various therapeutic approaches have been currently developed for the treatment of DMD patients. One of the most promising approaches is exon-skipping by antisense oligonucleotides. Four exon-skipping drugs, eteplirsen, viltolarsen, golodirsen, and casimersen, have been approved by the U.S. Food and Drug Administration (FDA). We have collaborated with Nippon Shinyaku Co., Ltd. to develop FDA-approved exon 53 skipping drug “NS-065/NCNP-01 (viltolarsen)”. Additionally, we have been developing other exon-skipping drugs, exon 44 skipping drug “NS-089/NCNP-02 (brogidirsen)”, exon 50 skipping drug “NS-050/NCNP-03”, and exon 51 skipping “NS-051/NCNP-04”, for patients not eligible for treatment with viltolarsen. In particular, brogidirsen was the first in the world to successfully restore the expression of dystrophin protein to more than 15% of normal in clinical trials. Notably, brogidirsen is the first exon-skipping drug to receive breakthrough therapy designation from the FDA. Vector-mediated therapy is also attractive approaches for DMD treatment. The review summarizes the latest therapeutic developments in exon-skipping and vector-mediated gene therapy for DMD.

The effects of the microgravity environment in space on skeletal muscles have been analyzed by various space experiments, but it has been technically difficult to scientifically analyze the threshold of gravity effects. To elucidate this problem, a small animal breeding apparatus with a centrifuge that can generate artificial gravity in the space environment was installed on the International Space Station. In collaboration with the Japan Aerospace Exploration Agency (JAXA), we used this apparatus to raise mice under several gravity environments and analyzed the effects of gravity on skeletal muscles. The results showed that, as expected, microgravity-induced muscle atrophy and increase of fast twice muscle fibers were completely suppressed in artificial 1g (earth gravity). On the other hand, 1/6 g (lunar gravity) suppressed muscle atrophy but not increase of fast twitch muscle fibers. These results suggest that muscle atrophy and myofiber change are independently regulated. To analyze the molecular mechanisms, gene expression analysis was performed to analyze the genes that fluctuate in response to the gravitational environment. From this analysis, we identified a previously uncharacterized Large Maf transcription factor that induces fast twitch muscle fibers. Overexpression of the Large Maf transcription factor in skeletal muscle induced fast-twitch type IIb fibers. Deletion of the Large Maf transcription factor in skeletal muscle resulted in little formation of type IIb fibers. Furthermore, this mechanism is conserved across animal species. These results indicate that the Large Maf transcription factor is a major transcription factor that induces Type IIb fibers across animal species.

As our population ages, muscle weakness associated with functional decline of skeletal muscles, such as sarcopenia, has become a problem. To address this, researchers are searching for food ingredients that can prevent muscle weakness. The process of searching for active ingredients usually involves efficacy evaluation tests using cultured cells. However, for evaluating ingredients that prevent muscle weakness, it is desirable to conduct efficacy evaluation using muscle strength as an indicator, which is difficult to measure with muscle cells cultured on a normal two-dimensional culture dish. Recently, research on microphysiological systems (MPS) has been active, and scientists have conducted efficacy evaluations using three-dimensional (3D) skeletal muscle tissue cultured on their own microdevice, using muscle strength as an indicator. In addition, the researchers investigated an evaluation system for 3D skeletal muscle tissue using primary human skeletal muscle cells, which is useful for evaluating human-derived cells rather than rodent-derived cells. This evaluation system is expected to be applied to research to evaluate the efficacy of food ingredients that contribute to the maintenance and improvement of skeletal muscle function. This paper describes the 3D culture system using a unique microdevice and introduces research on L-anserine, whose effect on improving muscle strength was confirmed in 3D skeletal muscle tissue using primary human skeletal muscle cells.

The extracellular matrix (ECM) not only functions as a physical scaffold for cells, but is also an essential component for tissue morphogenesis, differentiation, and homeostasis maintenance. Matrix metalloproteases (MMPs) function to maintain tissue homeostasis by degrading ECM proteins. In particular, in the skin, MMP contribute to ECM remodeling and angiogenesis during the wound healing process. The role of MMP in the cell invasion process of cancer cells has led to the development of MMP inhibitors, and the pathophysiology of MMP has also been actively studied. Recently, the mechanism by which senescence-associated secretory phonotype (SASP) factors, which are characteristically secreted by senescent cells, cause chronic inflammation and how a small number of senescent cells can have systemic effects has also attracted attention. SASP contains many MMP groups, and the role of MMPs in the aging process has been reconfirmed. In this review, we will provide an overview of aging and aging-related pathologies from the perspective of MMPs, and will also introduce the contribution of MMPs to the skin and various tissue aging in aging model mice that the authors are analyzing.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are omega-3 polyunsaturated fatty acids abundant in fish oil. DHA and EPA have been reported to have antithrombotic effects, prevent cardiovascular diseases, and reduce serum triglycerides and total cholesterol levels; however, their effect on bone metabolism remains unclear. We investigated the effects of DHA and EPA on inflammatory bone resorption. We found that DHA and EPA inhibited osteoclast differentiation in a coculture system of mouse osteoblasts and bone marrow cells. Additionally, in primary mouse osteoblasts, DHA and EPA suppressed the production of the inflammatory mediator prostaglandin E2 (PGE2) and the gene expression of receptor activator of nuclear factor kappa-B ligand (RANKL). In Raw264.7 cells, DHA and EPA inhibited RANKL-induced osteoclast differentiation and suppressed the mRNA expression of osteoclast differentiation marker genes, such as cathepsin K and Clc-7.

Lutein, a member of the xanthophyll family of carotenoids, is abundantly contained in green and yellow vegetables and fruits. High concentrations of lutein exists in the macula, and it prevents eye diseases such as macular degeneration and cataracts through antioxidant effects and blue light absorption. However, the effect of lutein on bone metabolism remains unclear. Bone tissues are constantly resorbed by osteoclasts and regenerated by osteoblasts. The imbalance between bone resorption and bone formation results in bone-related diseases such as osteoporosis. We found lutein suppressed RANKL expression in osteoblasts, preventing inflammatory osteoclast differentiation and bone resorption. In vivo studies showed that feeding lutein to growing mice increased peak bone mass. In this review, we summarize the regulatory effects of lutein on bone metabolism and introduce the potential of lutein as a functional food to maintain the bone health.

Appropriate exercise and nutritional intake are required to maintain the health of locomotor system, including skeletal muscle, in aged people. Sarcopenia, characterized by age-related loss of skeletal muscle mass and function, can be prevented by both exercise and nutritional approaches; however, the mechanism remains unclear. Branched-chain amino acids (BCAA) intake after resistance training promotes muscle protein synthesis, and free BCAA in blood and cells have been reported to exhibit various physiological functions. Most ingested amino acids are metabolized in the liver, while BCAA are metabolized in skeletal muscle. Recently, metabolites derived from L-leucine, one of the BCAA, have been shown to activate mTORC1 (mechanistic target of rapamycin complex 1) pathway and accelerate myogenesis. In this review, we summarize the effects of BCAA and mechanical stimulation on skeletal muscle cells.

In this study, a cross-over study was conducted to clarify the effects of food properties (warm, hot, cold, cool, and plain) on coldness based on Chinese medicine nutritional science. The study period was from April 2021 to July 2021. The subjects were 15 female university students (ages 19-26) who were diagnosed as having sensitivity to cold according to the diagnostic criteria for sensitivity to cold symptoms. Subjects were divided into two groups: 8 subjects who had taken bread for breakfast as group A and 7 subjects who had taken rice as group B on a daily basis. The test foods were bread (wheat; cool) and red rice (glutinous rice; warm). The body composition of subjects was measured, then subjects consumed each of the test foods for breakfast for 2 weeks. Cold water stress test (hand), blood pressure, and axillary temperature were measured before and 2 weeks after consumption of each test food. Results were calculated and analyzed using SPSS (Ver. 27). There was no difference in body size and composition between group A and group B. Comparing the group A and B before the dietary intervention, axillary temperature was significantly higher in the group B (p < 0.05), suggesting that intake of rice for breakfast may maintain a higher body temperature. In the A group, there was no effect of bread intake on skin temperature recovery rate, blood pressure, or body temperature, but 2 weeks of red rice intake significantly increased axillary temperature (p < 0.05). In the group B, no changes were observed before or after test foods intake. The axillary temperature increased when daily bread-eaters into red rice, suggesting that a foods based on Chinese medicine nutritional science may have an influence on the improvement of cold symptoms.

Reactive oxygen species (ROS) generated by aging, genetic factor and the external factors such as ultraviolet rays are one of the causes of accelerated aging. CuZn-superoxide dismutase (CuZn-SOD, SOD1) localizes in the cytoplasm and plays an important role in maintaining redox homeostasis in cells. In fact, SOD1-deficient mice exhibit various aging-like changes such as skin atrophy, fatty liver and muscle atrophy. In this study, we estimated the anti-aging effects of curcumin, functional food containing curcumin, ginkgo biloba extract, L-carnitine, long pepper extract and astaxanthin and a sake extract including thioredoxin (TRX) on SOD1-deficient mice. These foods were administered orally to SOD1-deficient mice for 8 weeks and observed aging-like changes. Functional food, but not curcumin only, significantly improved the decrease in skin thickness. In addition, this food treatment significantly suppressed the increase in 8-isoprostane, an oxidative stress marker, and tended to suppress the upregulation of matrix metalloproteinase-2 (MMP-2). On the other hand, sake extract containing TRX significantly suppressed the skin atrophy and enlargement of the liver in the mutant mice. These results suggest that functional foods with antioxidant and anti-inflammatory activity can improve the aging-like phenotypes of the SOD1-deficient mice.

Fermentation using koji mold has garnered attention in recent years for its capacity to produce beneficial substances. Green tea fermented with koji mold yields polyphenols with whitening effects. Persimmon leaf tea, known as Kakinoha-cha, contains ingredients similar to green tea; however, it contains higher levels of gallic acid. Given that the inhibitory effect (IC50) of gallic acid against tyrosinase is similar to that of kojic acid, which is known for its activity as a tyrosinase inhibitor, persimmon leaf tea itself can be said to have high tyrosinase inhibitory activity. Additionally, persimmon leaf tea contains gallate catechins, akin to green tea, which are decomposed by yeast into gallic acid and hydrolyzed catechins. Therefore, persimmon leaf tea inherently possesses high tyrosinase inhibitory activity. Consequently, fermentation of persimmon leaf tea using koji mold is expected to have a stronger whitening effect than green tea because of the increased formation of gallic and kojic acid levels and their tyrosinase inhibitory activity. In this study, we fermented persimmon leaf tea using Aspergillus Oryzae (NBRC30113, RIB40) and Aspergillus Awamori (NBRL 4388) for seven days and evaluated its whitening effect and the associated factors. The evaluation of whitening action involved assessing its tyrosinase inhibitory activity. Inhibitory factors, the levels of kojic acid and total polyphenols in fermented persimmon leaf tea were assessed, followed by an investigation into their respective tyrosinase inhibitory activities. Results showed a significant increase in tyrosinase inhibitory activity after four days for the fermentation using NBRC30113 and RIB40, and after six days for NBRL 4388. Total polyphenol content exhibited an increasing trend during the seven-day fermentation, whereas kojic acid content remained unchanged. Comparison of tyrosinase inhibitory activity between 45 mg/L gallic acid solution and 0.03 mg/mL kojic acid solution (the highest concentration in this experiment), revealed higher activity with gallic acid suggesting that polyphenols play a significant role in the tyrosinase inhibitory activity of fermented persimmon leaf tea.

The tip of leaf blade from Green onion (Allium fistulosum L.) has been cut and thrown away for distribution. In order to utilize the discarded leaf blade parts, the effect of its ingestion on photoaging skin has been studied. The skin aging model has made by UVB irradiated hairless mice to increase intensity gradually. The photoaging skin mice were orally administered of ground leaf blade and water extracts of leaf blade from green onions, and the moisture contents and transepidermal water loss (TEWL) of photoaging mice back skins were measured. To analyze the constituents of the green onion extract, the extract was analyzed using reversed-phase chromatography, mass spectrometry, and thin-layer chromatography. Administration of crushed green onion and green onion extracts to a photoaging mice inhibited the decrease in back skin water content and epidermal thickening, both of which had been produced by UV exposure. In addition, in the green onion aqueous extract inhibited the formation of wrinkles in the back skin and increased the amount of type I collagen. Component analysis of green onion extract showed the presence of glucose-containing polymers. It was also revealed that the green onion extracts do not contain quercetin. So it has been suggested that components other than quercetin in green onions suppress the photoaging skin.

An internet survey was conducted in November 2017 and March 2018 with the aim of clarifying the level of understanding regarding foods with health claims (foods for specified health uses, food with nutrient function claims, foods with function claims). The subjects were 300 general consumers and 392 medical workers (pharmacists, registered dietitians, nurses). The items of survey included the subject's attributes (gender, age), experience of using health foods, awareness and knowledge of the contents of foods with health claims. Health foods in this study were defined as “foods with health claims and all foods intended to maintain and improve health''. From results of this study, more than half of all subjects had experience using health foods. Approximately 20% of general consumers answered that they think health foods are medicines or similar to medicines. General consumers had the lowest level of awareness and knowledge of the three types of foods with health claims. There were differences in the degree of awareness and understanding among medical workers depending on the type of job. Registered dietitians tended to have higher awareness and knowledge than pharmacists and nurses. Among foods with health claims, awareness of foods for specified health uses was high in all groups. This was thought to be due to the reason that more than 20 years have passed since the system was started. On the other hand, awareness of foods with function claims, which the system was started in 2015, tended to be low in all groups. These results indicate that knowledge of foods with health claims may not be sufficient, even among medical workers. From now on, information sharing among medical workers will be necessary to ensure the appropriate and safe use of foods with health claims. Simultaneously, it is necessary to establish a new system for providing information on health foods including foods with health foods. It is also expected that general consumers to take responsibility for their own health, collect their own information, and use health food handbooks (Consumer Affairs Agency).

There are many papers to intake of collagen hydrolysate improves dry skin. In this study, 38 volunteer who are interested in taking collagen were participated to ingestion of fish skin-derived collagen peptide. The volunteers ingested the test food for 8 weeks. Their blood biochemistry tests, blood Pro-Hyp levels, skin moisture levels, and stratum corneum water loss (TEWL) were measured before, 4, and 8 weeks after ingestion. Three groups were set up for the subjects: "ingestion of 2.5 g group with fish skin-derived collagen peptide", "ingestion of 12.5 g group with fish skin-derived collagen peptide", and placebo group. A randomized double-blind parallel group comparison study was conducted. As a result, no changes were observed in blood albumin levels, γ-GT levels, and other indicators after ingestion of 2.5 and 12.5 g with collagen peptide compared to before ingestion. Even taking 12.5 g, which is five times the usual amount, there was no change in blood biochemistry data, confirming safety. Blood Pro-Hyp levels were higher after ingestion of collagen peptide, but no effect was observed on blood collagen levels. Although there was no statistical significance, skin moisture content after two months was higher in the collagen peptide ingestion group compared to the placebo group. In addition, TEWL after two months was lower in the collagen peptide 2.5g ingestion group compared to the placebo group. Therefore, negative effect was not observed from administering a five-fold excess of collagen peptide, suggesting the possibility of an increase in skin moisture content and enhanced skin barrier function.