Muscle-increasing agent with GABA as active ingredient

Abstract

To provide a muscle-increasing agent which can daily and continuously be taken and is for increasing muscle strength and maintaining muscle strength of middle-aged and elderly persons.SOLUTION: There are provided an agent containing GABA as an active ingredient, which can increase muscle strength represented by knee extension muscular strength which is necessary for maintaining ability to stand and walk by combination of GABA intake and light exercise, and a food and drink composition for increasing muscle strength, which contains GABA as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the technical field of increasing muscle strength or maintaining muscle strength in middle-aged and elderly people. [Background technology]

[0002] Although the average life expectancy of Japanese people is over 80 years old for both men and women, the "healthy life expectancy" - the period during which they can live independently and in good health - is in the 70s for both men and women, and it is said that there will be around 10 years during which they will require some form of nursing care. Falls and frailty due to old age are reasons why elderly people become dependent on nursing care, and the decline in muscle mass and strength that accompanies aging is attracting attention as a risk factor for these.

[0003] It is said that muscle strength begins to decline around the age of 40. As fat infiltrates muscle cells with age, it is now recognized that muscle mass and muscle strength are different. Muscle strength is muscle quality and is the most reliable indicator of muscle function. It has been proven that muscle strength is effective in maintaining mobility, such as being able to stand up from a lying down position, sit in a chair, or stand up from a sitting position, as well as walking ability.

[0004] Gamma-aminobutyric acid (GABA) is a non-proteinogenic amino acid widely distributed in nature, and is an inhibitory neurotransmitter found in large quantities in the central nervous system of mammals. It became available for use as a food in 2001 with the revision of the food and drug classification, and has been reported to have a wide range of physiological effects, including stress relief by improving autonomic nervous system balance, improving sleep quality, and maintaining skin elasticity. GABA has been reported to promote the secretion of growth hormone, and based on this effect, Non-Patent Document 1 reports that in a study in which healthy men (26-48 years old) took in 10g of whey protein and 100mg of GABA daily and performed resistance training at a fitness club at 60% of their maximum intensity twice a week for 12 weeks, lean body mass measured by dual-energy X-ray absorptiometry (DEXA) increased significantly compared to a placebo, but knee extension strength did not increase significantly compared to a placebo.

[0005] Non-Patent Document 2 reports that middle-aged women who refrain from regular exercise took fermented kelp containing 54.5 to 0.071 mg of GABA for eight weeks, resulting in a significant increase in lean body mass (DEXA) compared to the placebo group, and Patent Document 1 describes a muscular endurance-improving composition containing GABA, which enhances the endurance-improving effect of training. It also describes that this endurance-improving effect is limited to when GABA is taken in conjunction with exercise load through training, and that GABA taken without exercise load is ineffective.

[0006] Furthermore, Patent Document 2 describes an agent containing GABA as an active ingredient for promoting the expression of muscle synthesis-related genes, promoting muscle synthesis, suppressing the expression of muscle atrophy-related genes, suppressing muscle atrophy, or suppressing muscle protein breakdown. Although it has been reported that taking GABA while exercising can improve endurance and increase muscle mass by promoting growth hormone secretion, it is not known that GABA alone can increase muscle strength or maintain muscle strength in middle-aged and older people, regardless of whether or not exercise is performed. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent Publication No. 2021-132645 [Patent Document 2] Patent No. 7308329 [Non-patent literature]

[0008] [Non-Patent Document 1] J. Clin. Med. Res. (2019) Vol.11, No.6, p.428-434 [Non-patent document 2] Algae (2016) Vol.31, No.2, p.1-13 Summary of the Invention [Problem to be solved by the invention]

[0009] The problem to be solved by the present invention is to provide an agent that can be taken continuously on a daily basis and that can effectively increase muscle strength, and a food and drink composition for increasing muscle strength. [Means for solving the problem]

[0010] As a result of extensive research, the present inventors have discovered that γ-aminobutyric acid (GABA) has the effect of increasing muscle strength and maintaining muscle strength in middle-aged and elderly people, and have thus completed the present invention.

[0011] The present invention relates to the following muscle-strength-increasing agents (1) to (5) or muscle-strength-increasing food and drink compositions (6) and (7). (1) A muscle-strengthening agent whose active ingredient is GABA. (2) The agent described in (1) above, which increases muscle strength in middle-aged and elderly people. (3) The agent according to (1) or (2) above, which increases knee extension muscle strength. (4) The agent according to (1) or (2) above, which is a formulation for oral administration. (5) The agent according to (1) or (2) above, wherein the daily intake of GABA is 10 to 3000 mg. (6) A food and beverage composition for increasing muscle strength, containing GABA as an active ingredient. (7) The food and beverage composition described in (6) above, which is for increasing knee extension muscle strength. [Effects of the Invention]

[0012] According to the present invention, a new muscle-strengthening agent that can be taken on a daily basis can be provided. No side effects have been reported to date, and the active ingredient is safe GABA, which can be used as a food ingredient, so it can be administered and taken continuously over a long period of time. As muscle cells become infiltrated with age, muscle mass and muscle strength become inconsistent in middle-aged and elderly people over the age of 40. Increasing muscle strength is effective in maintaining mobility, such as being able to stand up from a lying down position, sit in a chair, or stand up from a sitting position, as well as walking ability. Therefore, this compound can be used as a health food, food and drink, or medicine to improve the quality of life (QOL) of middle-aged and elderly people and prevent them from becoming bedridden. DETAILED DESCRIPTION OF THE INVENTION

[0013] GABA in the present invention is an abbreviation for γ-amino butyric acid. It is an amino acid widely distributed in plants and animals, and is an inhibitory neurotransmitter present in the brain and spinal cord of mammals. GABA improves cerebral blood flow, increases oxygen supply, and enhances cerebral metabolism, making it useful in treating headaches, tinnitus, and loss of appetite caused by stroke, head trauma, and cerebral artery disorders. Other known physiological effects include improved learning ability and renal activation. GABA is primarily found in the brain of living organisms and is involved as a neurotransmitter in the central nervous system. It is known as the primary inhibitory neurotransmitter and is used to activate blood flow in the diencephalon, enhance the metabolic function of brain cells, and alleviate autonomic nervous system stress.

[0014] The GABA in the present invention is GABA contained in vegetables, fruits, grains, etc., or GABA extracted from them, GABA produced from fermented foods, or GABA produced by organic synthesis. The above vegetables, fruits, and grains refer to pumpkin, eggplant, tomato, cucumber, rice, brown rice, malt, soybeans, etc., and fermented foods refer to fermented foods such as kimchi, pickles, fermented milk, and natto, which are derived from lactic acid bacteria, yeast, and natto bacteria. They can be obtained by fermenting germ rice, green tea, or rice bran with lactic acid bacteria, or by fermenting glutamic acid with lactic acid bacteria. They can also be obtained by enzymatically converting glutamic acid and / or monosodium glutamate using naturally occurring glutamic acid decarboxylase (GAD), or by isolating bacteria from fermented foods and preparing them in a culture medium.

[0015] The muscle-building agent of the present invention is preferably used in oral compositions, foods and beverages (supplements), and food additives. When the muscle-building agent of the present invention is used as a supplement or medicine, it is preferably used in oral compositions such as tablets, powders, granules, capsules, and liquids containing excipients. Oral compositions may be sublingual medicines (not only tablets, but also wafer-like sheets and pastes), jellies, or drinks containing suspended fine powders. Furthermore, food and beverage compositions and pharmaceutical compositions are not limited to those for humans, but also include those for mammals such as dogs and cats kept as pets or livestock.

[0016] GABA may be used in the form of foods and beverages rich in GABA. The form of such foods and beverages is not particularly limited, and may be formed into powder, granules, capsules, or tablets. Other forms include food ingredients, food additives, syrups, suspensions, energy drinks, liquid diets, soft drinks, milk drinks, lactic acid bacteria drinks, functional seasonings, gel foods, puddings, yogurt, sweets and cakes, breads, noodles, pasta, chocolate, candy, chewing gum, and the like. In addition to regular foods and beverages, the food and beverage category also includes supplements, health foods, enteral nutritional foods, functional foods, and foods for specified health uses.

[0017] The daily intake of GABA of the present invention as a food, drink, or medicine is preferably 10 to 3,000 mg, and foods and drinks containing GABA as an active ingredient may contain 10 to 90 wt %, preferably 25 to 50 wt %, of GABA as an active ingredient. The daily intake of such foods and drinks per adult is in the range of 10 to 5,000 mg, preferably 250 to 3,500 mg.

[0018] To verify the effectiveness of the human muscle-strengthening agent of the present invention, a randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted. Fifty subjects (aged 40 years or older) were randomly assigned to either a group receiving a GABA-containing diet (100 mg / day) or a placebo diet. The subjects orally ingested each test substance daily for 12 weeks. They underwent a daily "Loco-Training" program designed by the Japanese Orthopaedic Association, and muscle mass, fat mass, knee extension strength, and other parameters were measured before, 6, and 12 weeks after the start of intake.

[0019] The Japanese Orthopaedic Association has developed a "two-step test" to assess the severity of locomotive syndrome. The two-step test is introduced on the association's official locomotive syndrome prevention and awareness website, and is also introduced on the Ministry of Health, Labor and Welfare's website. The two-step test is highly reliable and an excellent method for assessing walking ability, examining step size and height, muscle strength, balance ability, and lower limb flexibility. The score is calculated by dividing the length (cm) of two steps by the height (cm).

[0020] The Japanese Orthopaedic Association defines individuals with a 2-step test score of 0.9 or greater but less than 1.1 as having locomotive syndrome level 2. Level 2 individuals experience a gradual decline in motor ability and a higher risk of being unable to lead an independent lifestyle. Individuals with a 2-step test score of 1.1 or greater but less than 1.3 are defined as having locomotive syndrome level 1, meaning their motor ability is beginning to decline but can be improved through diet and exercise. This study targeted men and women with locomotive syndrome level 1, defined as individuals with a 1-step test score of 1.1 or greater but less than 1.3. The subjects were healthy men and women aged 40 or older who were aware of age-related muscle weakness, had a 2-step test score of 1.1 or greater but less than 1.3 during the 0-week pre-treatment test, and voluntarily agreed to participate in the study after fully understanding its purpose and content.

[0021] From the start of supplementation until the day before the 12-week test, subjects performed "Loco-Training," a program developed by the Japanese Orthopaedic Association, at home for approximately 20 minutes per day. The "Loco-Training" consisted of three exercises: one set of one-minute single-leg standing on each side, one set of five squats, and one set of 10 front lunges on each side. Subjects performed three sets of "Loco-Training" exercises per day to stimulate the muscles of the lower body. The intensity level of exercise was measured in metabolic equivalents (METs). One MET is defined as the amount of oxygen consumed at rest and is equivalent to 3.5 mL of O2 per kg of body weight per minute. The METs for lower-body exercise in this study were 2.11 ± 0.44 for single-leg standing, 6.5 ± 1.1 for squats, and 8.5 ± 0.1 for front lunges. A fairly slow walk is equivalent to 2 METs, and for adults aged 41 to 60, walking at a speed of 130 steps per minute is equivalent to 6 METs. Running at a speed of 134 m / min is equivalent to 8 METs. Before intake, and 6 and 12 weeks after starting intake, the subjects' muscle mass, fat mass, knee extension strength, etc. were measured and they were interviewed.

[0022] The results of a randomized, double-blind, placebo-controlled, parallel-group comparative study showed no significant differences in muscle mass or body fat mass between the two groups.Compared to the placebo group, the GABA group showed a significant increase in knee extension strength in either the right or left leg, whichever was higher for each subject in the test before initiating supplementation (week 6: p = 0.02). In a post-hoc subgroup analysis by gender, compared to the placebo group, in men, the GABA intake group showed a significant increase in right leg knee extension strength (week 6: p = 0.001, week 12: p = 0.007), left leg knee extension strength increased significantly at week 6 (p = 0.02), and the knee extension strength of either the right or left leg that was higher for each subject in the pre-supplementation test increased significantly at week 6 (p = 0.001), and the knee extension strength of either the right or left leg that was lower for each subject in the pre-supplementation test increased significantly at week 12 (p = 0.013).

[0023] The study suggests that combining GABA intake with daily light exercise, such as 20 minutes of exercise at a load of 2-9 METs, is effective in maintaining knee extension strength, which declines with age. Furthermore, no safety issues were found with the intake of foods containing GABA during this study. As muscle cells become infiltrated with age, fat infiltrates, and muscle mass and strength do not align in middle-aged and elderly people over the age of 40. It has been shown that GABA intake in combination with light exercise such as locomotion training can increase muscle strength, particularly knee extension strength.

[0024] Below, we will explain in detail the randomized, double-blind, placebo-controlled, parallel-group comparative study and its measurement results. [Test food] The test food was a hard capsule containing 100 mg of GABA. The source of GABA was barley lactic acid fermentation filtrate GABA 90% (Sanwa Shurui Co., Ltd.). The placebo food contained starch instead of GABA and was visually indistinguishable from the test food. Other ingredients in the capsules were starch, milk calcium, microcrystalline cellulose, cyclic oligosaccharides, and sucrose esters.

[0025] [subject] Of the 200 subjects who provided written consent, 150 subjects were excluded from the pre-administration test, and 50 subjects who met the inclusion criteria were selected. All 50 subjects took the test food and completed all prescribed study schedules and procedures. Therefore, all 50 subjects, including 25 subjects in the test food intake group (Group A) and 25 subjects in the placebo food intake group (Group P), were included in the safety evaluation analysis. One subject developed acute low back pain before the Week 6 examination and discontinued exercise training, so the Week 6 examination results were not submitted. These were treated as missing data, and 49 subjects (24 in Group A and 25 in Group P) were included in the efficacy analysis.

[0026] [Subject background] Pre-treatment week 0 values ​​for the per-protocol analysis set of 49 subjects are shown in Table 1. "Group A" and "Group P" refer to the GABA food intake group and the placebo food intake group, respectively. Values ​​are expressed as mean ± standard deviation (excluding number of subjects and gender). Comparisons between groups were performed using two-sample t-tests, and comparisons between men and women were performed using chi-square tests.

[0027] [Table 1]

[0028] [Primary endpoint (body composition and lean body mass measurement)] Table 2 shows the actual muscle mass and body fat mass measured at week 0 before administration, and the changes at weeks 6 and 12. Significant differences in one-sample t-tests for changes within groups compared to week 0 before administration are expressed as **p < 0.01 and *p < 0.05. There were no significant differences between the groups in the amount of change in any of the items at weeks 6 and 12. In intragroup comparisons with week 0 before administration, body fat mass was significantly reduced in Group A at weeks 6 and 12, and in Group P at week 12. There were no significant differences in other items at any of the time points evaluated.

[0029] [Table 2]

[0030] [Knee extension strength measurement] Table 3 shows the knee extension strength values ​​divided by body weight on the day of testing and multiplied by 100. The right or left leg with the higher knee extension strength value at week 0 was designated the "dominant leg," and the leg with the lower knee extension strength value at week 0 was designated the "non-dominant leg." The change in the dominant leg (Group A: 11.17 ± 8.01%, Group P: 4.86 ± 7.40%, p = 0.02) at week 6 was significantly higher in Group A compared with Group P. Intragroup comparisons with week 0 before treatment showed significant increases in all items at weeks 6 and 12 in both groups. Comparisons between groups were performed using the Mann-Whitney U test. Significant differences in the Wilcoxon signed-rank test for within-group changes compared to pre-treatment week 0 were expressed as **p < 0.01, *p < 0.05.

[0031] [Table 3]

[0032] [Growth hormone levels] Because there were significant differences between the groups in the actual values ​​measured at week 0 before administration, analysis of covariance was performed. There were no significant differences between the groups in the changes in any of the items at weeks 6 and 12. Intragroup comparisons with week 0 before administration showed no significant differences in any of the items at any time points evaluated.

[0033] [summary] In this study, healthy individuals aged 40 or older who were aware of muscle weakness and whose muscle weakness was objectively demonstrated by a two-step test took GABA in combination with lower body exercise, and no significant differences were observed in lean body mass or growth hormone levels. Meanwhile, the GABA supplementation group showed a significant increase in knee extension strength compared to the placebo group at week 6. Locomotion training is known to improve knee extension strength in elderly people, but the combination of GABA supplementation and locomotion training significantly improved knee extension strength compared to locomotion training alone.

[0034] Exercise and GABA intake correlate with muscle mass and muscle quality. When examining the effects on muscle strength, GABA intake with loco-training showed no significant difference in muscle mass compared to the loco-training group that did not take GABA, but showed a significant increase in knee extension strength. In the GABA intake group, training reduced intramuscular lipids, and training and GABA intake increased the number of myotubes and muscle fibers, presumably increasing muscle density overall. This could explain why the GABA intake group showed a significant increase in knee extension strength in group comparison.

[0035] In this study, healthy men and women aged 40 years or older who were assessed as having locomotive syndrome level 1 were given GABA and engaged in lower body exercise training. Knee extension strength significantly increased after six weeks. In particular, knee extension strength in men significantly improved after six and 12 weeks. Therefore, it was shown that the combination of oral GABA intake and lower body exercise is effective in maintaining mobility (ability to stand up from a lying down position, sit in a chair, and stand up from a sitting position) and walking ability in people aged 40 years or older, particularly men.

Claims

1. A muscle-strengthening agent whose active ingredient is GABA.

2. The agent according to claim 1, which is for increasing muscle strength in middle-aged and elderly people.

3. The agent according to claim 1 or 2, which increases knee extension muscle strength.

4. The agent according to claim 1 or 2, which is a formulation for oral administration.

5. 3. The agent according to claim 1, wherein the daily intake of GABA is 10 to 3000 mg.

6. A food and drink composition for increasing muscle strength, containing GABA as an active ingredient.

7. The food and drink composition according to claim 6, which is for increasing knee extension muscle strength.

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