JP6288757B2 - Motor function improver - Google Patents
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Description
本発明は、グルタチオンを有効成分として含む運動機能性向上剤に関する。 The present invention relates to a motor function improver containing glutathione as an active ingredient.
通常、運動を行なうと、筋肉にあるグリコーゲン由来のグルコースが利用され、無酸素的な解糖反応が進行して筋肉の収縮に必要なＡＴＰが合成される。その代謝産物である乳酸が蓄積することで筋肉中のｐＨ低下し、筋収縮の効率が落ちてくる。このため、筋肉中のpＨを低下させないことが運度機能を持続させるためには必要となる。 Normally, when exercise is performed, glycogen-derived glucose in muscle is utilized, and an anaerobic glycolysis reaction proceeds to synthesize ATP necessary for muscle contraction. Accumulation of lactic acid, which is a metabolite, lowers the pH in the muscle and reduces the efficiency of muscle contraction. For this reason, it is necessary to maintain the mobility function not to lower the pH in the muscle.
また、骨格筋のエネルギー代謝制御に関与する因子ＰＧＣ−１αが知られている（非特許文献１）。マウスを寒冷環境下におくと骨格筋でのＰＧＣ−１αが増加する。そのため骨格筋組織での熱産生の制御に関わることが知られている。また、ＰＧＣ−１αを強制発現させると、ミトコンドリア呼吸鎖に関わる因子の転写を促すＮＲＦや、ミトコンドリアにおいてエネルギー消費を起こすと考えられている脱共役蛋白質、ｕｎｃｏｕｐｌｉｎｇ ｐｒｏｔｅｉｎ（ＵＣＰ）の発現が誘導されるほか、ミトコンドリアのゲノム複製や転写反応過程に重要な役割を果たすｍｉｔｏｃｈｏｎｄｒｉａｌ ｔｒａｎｓｃｒｉｐｔｉｏｎ ｆａｃｔｏｒ Ａ（ｍｔＴＦＡ）の発現が誘導され、これら分子の機能発現によって細胞内のミトコンドリア数が増加し、また細胞の酸素消費量が増大することも明らかとなった。このことから、ヒト由来細胞内において、ミトコンドリアの機能が活性化することで、熱産生、即ちエネルギー消費を引き起こし、さらには細胞内でエネルギー源となる糖や脂質の代謝を活性化させることが知られている（非特許文献２）。 In addition, a factor PGC-1α involved in the energy metabolism control of skeletal muscle is known (Non-Patent Document 1). When the mouse is placed in a cold environment, PGC-1α in skeletal muscle increases. Therefore, it is known to be involved in the control of heat production in skeletal muscle tissue. In addition, forced expression of PGC-1α induces the expression of NRF that promotes transcription of factors related to the mitochondrial respiratory chain and uncoupling protein (UCP), which is thought to cause energy consumption in mitochondria. In addition, the expression of mitochondrial transcription factor A (mtTFA), which plays an important role in mitochondrial genome replication and transcription reaction processes, is induced, and the functional expression of these molecules increases the number of mitochondria in the cell, and the oxygen consumption of the cell. It has also been revealed that increases. From this, it is known that activation of mitochondrial functions in human-derived cells causes heat production, that is, energy consumption, and also activates metabolism of sugars and lipids that are energy sources in the cells. (Non-Patent Document 2).
これまで、運動機能改善剤について、抗疲労剤として、ビタミン類（特許文献１）、カツオやマグロの多量に含まれるイミダゾール化合物（特許文献２）、オルニチン（特許文献３）などが知られている。抗酸化物質として知られているグルタチオンは、特許文献３では、オルニチンと相乗効果により、ストレス性抗疲労効果があることが記載されている。 Until now, vitamins (Patent Document 1), imidazole compounds (Patent Document 2), ornithine (Patent Document 3) contained in large amounts of bonito and tuna are known as anti-fatigue agents for motor function improvers. . Glutathione, which is known as an antioxidant, is described in Patent Document 3 as having a stress anti-fatigue effect due to a synergistic effect with ornithine.
しかし、グルタチオンが、運動機能を維持、向上させることについては、これまで知られていなかった。 However, it has not been known so far that glutathione maintains and improves motor function.
本願発明は、安全な物質で運動機能を維持、向上させる、運動機能向上剤を提供することを課題とする。 This invention makes it a subject to provide the motor function improving agent which maintains and improves motor function with a safe substance.
本願発明者らは、グルタチオンに筋肉中のpＨの低下を抑制する機能と、ＰＧＣ−１αを活性化し、ミトコンドリアＤＮＡの産生量が増加することを見出し、本願発明を完成させた。 The inventors of the present invention have found that glutathione has a function of suppressing pH reduction in muscle and that PGC-1α is activated to increase the production amount of mitochondrial DNA, thereby completing the present invention.
本発明は、
（１）グルタチオンを有効成分として含む、ミトコンドリア活性（ミトコンドリアDNA量増加）による運動機能性向上剤、
（２）グルタチオンを有効成分として含む、筋肉ｐH低下抑制による運動機能性向上剤、
（３）グルタチオンを有効成分として含む、ミトコンドリア活性（ミトコンドリアＤＮＡ量増加）及び筋肉ｐＨ低下抑制による運動機能性向上剤。
を提供する。
The present invention
(1) an agent for improving motor function by mitochondrial activity (increased mitochondrial DNA), comprising glutathione as an active ingredient,
(2) An agent for improving motor function by suppressing muscle pH reduction, comprising glutathione as an active ingredient,
(3) An agent for improving motor function, comprising glutathione as an active ingredient, by suppressing mitochondrial activity (increasing mitochondrial DNA) and reducing muscle pH.
I will provide a.
本発明により、筋肉中のpＨ低下を抑制する効果により、運動機能を持続させることができる。また、PGC-1αの活性化によりミトコンドリアが活性化するため、体内中の脂肪の取り込みや脂肪の燃焼が効率的に進むため、運動機能の維持だけでなく、体内の脂肪代謝を促進する効果を有する。そのため、糖尿病などの生活習慣病を予防する効果も有する。
According to the present invention, the motor function can be sustained by the effect of suppressing the pH drop in the muscle. In addition, since the activation of PGC-1α activates mitochondria, the intake of fat in the body and the burning of fat progress efficiently, so it not only maintains motor function but also promotes fat metabolism in the body. Have. Therefore, it also has an effect of preventing lifestyle-related diseases such as diabetes.
本発明の運動機能向上とは、疲労を抑制することではなく、競技等における運動実行力の向上から一般的なジョギング、ウオーキングのような軽度の運動実行力を向上させる機能である。また、運動時だけでなく平常時や歩行等の日常生活における体内の脂肪代謝を促進する機能も含む。 The improvement of the exercise function of the present invention is a function of improving a light exercise execution force such as general jogging and walking from the improvement of the exercise execution force in competition or the like, not suppressing fatigue. Moreover, the function which promotes fat metabolism in the body not only at the time of exercise but also in daily life such as normal time and walking is included.
本願発明の筋組織中のpＨ低下抑制とは、一般的には、筋組織中の乳酸の蓄積により筋肉中のｐHが低下し、酸性化する。筋組織中のｐＨが低下することにより、筋組織の代謝活性が低下し、運動を持続することができなくなる。本発明は、筋組織中のｐＨ低下を抑制するため、運動を持続させることが可能であり、さらに運動だけでなく、日常生活における歩行等においても、同様な効果を有するため、日常生活におけるグルコース等の消費が活発化する。 The suppression of pH decrease in muscle tissue of the present invention generally means that the pH in muscle decreases due to the accumulation of lactic acid in muscle tissue, resulting in acidification. When the pH in the muscle tissue is lowered, the metabolic activity of the muscle tissue is lowered and the exercise cannot be continued. Since the present invention suppresses the decrease in pH in muscle tissue, it is possible to continue exercise, and it has the same effect not only in exercise but also in walking in daily life. Etc. will be activated.
pＧＣ1αとは、Peroxisome proliferator-activated receptor γ co-activator 1αであり、ミトコンドリアの合成を促進する働きを有すること、血液中のブドウ糖（血糖）を骨格筋に取り込む糖輸送体であるＧＬＵＴ４を増加させることがしられている。また、ヒトの筋肉でのＰＧＣ１α発現量が糖尿病や老化によってミトコンドリア機能とともに低下し、ＰＧＣ１αはエネルギー消費量の低下によるメタボリックシンドロームなどの生活習慣病の疾患治療標的となることが知られている。 pGC1α is Peroxisome proliferator-activated receptor γ co-activator 1α, which has the function of promoting mitochondrial synthesis, and increases GLUT4, a sugar transporter that takes glucose (blood sugar) in blood into skeletal muscle It has been done. In addition, it is known that the expression level of PGC1α in human muscle decreases with mitochondrial function due to diabetes and aging, and PGC1α is a therapeutic target for lifestyle-related diseases such as metabolic syndrome due to a decrease in energy consumption.
本発明は、筋組織中のｐＨ低下抑制機能とＰＧＣ１αを活性化することで、ミトコンドリアＤＮＡ量を増加させ、結果的にミトコンドリアの合成を促進している。そのため、本発明は、生活習慣病の予防として使用することもできる。 The present invention activates PGC1α and pH lowering suppression function in muscle tissue, thereby increasing the amount of mitochondrial DNA and consequently promoting mitochondrial synthesis. Therefore, this invention can also be used as prevention of a lifestyle-related disease.
本発明でいうグルタチオンは、グルタミン酸、システイン、グリシンの３アミノ酸から構成されるトリペプタイドである。また、還元型グルタチオン、酸化型グルタチオンあるいはこれらの混合物でもよい。還元型グルタチオンとはγ−Ｌ−Ｇｌｕ−Ｌ−Ｃｙｓ−Ｇｌｙの構造を有するトリペプチドを表し、酸化型グルタチオンとは還元型グルタチオン２ 分子がＳＳ結合により結合したものである。グルタチオンの形態は、グルタチオンを有効成分として含有するものであれば何でもよい。 Glutathione as used in the present invention is a tripeptide composed of three amino acids, glutamic acid, cysteine and glycine. Further, reduced glutathione, oxidized glutathione, or a mixture thereof may be used. Reduced glutathione represents a tripeptide having the structure of γ-L-Glu-L-Cys-Gly, and oxidized glutathione is obtained by binding two reduced glutathione molecules through SS bonds. The form of glutathione may be anything as long as it contains glutathione as an active ingredient.
本願の運動機能改善効果を得るためには、前段のグルタチオンを有効成分として含むものを投与する。投与の方法は、特に限定されず、経口投与、静脈内、腹膜内もしくは皮下投与等の非経口投与をあげることができる。具体的には、錠剤、散剤、顆粒剤、丸剤、懸濁剤、乳剤、浸剤・煎剤、カプセル剤、シロップ剤、液剤、エリキシル剤、エキス剤、チンキ剤、流エキス剤等の経口剤、又は注射剤、点滴剤、クリーム剤、坐剤等の非経口剤のいずれでもよい。 In order to obtain the effect of improving the motor function of the present application, one containing glutathione in the previous stage as an active ingredient is administered. The method of administration is not particularly limited, and examples thereof include oral administration, parenteral administration such as intravenous, intraperitoneal or subcutaneous administration. Specifically, oral preparations such as tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, fluid extracts, Or any of parenteral preparations such as injections, drops, creams, suppositories, etc. may be used.
グルタチオンを含有する酵母を経口投与することもできる。グルタチオンを多く含有する酵母としては「ハイチオンコーボＭＧ」（興人ライフサイエンス社製）、グルタチオンを含有する酵母エキスとしては「ハイチオンエキスＹＨ」（興人ライフサイエンス社製）などがある。 Yeast containing glutathione can also be administered orally. Examples of yeasts containing a large amount of glutathione include “Hythion Cobo MG” (manufactured by Kojin Life Sciences), and examples of yeast extracts containing glutathione include “Hythion Extract YH” (manufactured by Kojin Life Sciences).
本発明の投与量は、前述の機能が発現する量でれば特に限定されない。ヒトに投与する場合の投与量および投与回数は、投与形態、被投与者の年齢、体重等により異なるが、成人一日当り、グルタチオンを通常は５０ｍｇ〜３０ｇ、好ましくは１００ｍｇ〜１０ｇ、特に好ましくは２００ｍｇ〜３ｇとなるように一日一回乃至数回投与する。 The dose of the present invention is not particularly limited as long as it is an amount that exhibits the above-described function. When administered to humans, the dose and frequency of administration vary depending on the dosage form, age of the recipient, body weight, etc., but glutathione is usually 50 mg to 30 g, preferably 100 mg to 10 g, particularly preferably 200 mg per adult day. Administer once to several times a day to achieve ~ 3 g.
投与間隔は、特に限定されない。継続的に投与することが好ましい。通常は１日間〜 １年間、好ましくは１週間〜３ヶ月間である。なお、本発明の製剤は、ヒトだけでなく、ヒト以外の動物に対しても使用することができる。
The administration interval is not particularly limited. It is preferable to administer continuously. Usually, it is 1 day to 1 year, preferably 1 week to 3 months. The preparation of the present invention can be used not only for humans but also for animals other than humans.
以下に実施例により本発明をさらに詳しく説明するが、本発明はこれらの実施例により限定されるものではない。 The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
本発明及び実施例における測定条件は以下の通りである。
（筋組織ｐＨの測定）
麻酔後, 微小ガラス電極（ＣＭＮ−１４１, Chemical Instruments）を用いて前脛骨筋と腓腹筋の間質pHを測定した。
The measurement conditions in the present invention and examples are as follows.
(Measurement of muscle tissue pH)
After anesthesia, the interstitial pH of the anterior tibialis and gastrocnemius was measured using a micro glass electrode (CMN-141, Chemical Instruments).
（ＰＧＣ−１α活性の測定）
筋中のＰＧＣ−１α量をwestern-blottingにより測定した。安静群の平目筋をホモジナイズし, ＢＣＡ法（BCATM Protein Assay Kit, Thermo SCIENTIFIC）を用いてタンパク質濃度を測定した。調製したタンパク質サンプルを１０％ゲル（Ｗａｋｏ）に流し込み, 電気泳動により分離し, 転写装置（iBlot, Invitrogen）を用いてメンブレンに転写した。３０分間のブロッキング後（EzBlockChemi, ATTO CORPORATION）, Tris buffered saline（BIO-RAD Laboratories）-Tween20（Wako）、ＴＢＳ−Ｔで５分間, ３回洗浄し, １次抗体にａｎｔｉ−ＰＧＣ−１α抗体（CHEMICON International）を用いて室温で６０分間反応させた。ＴＢＳＴで５分間, ３回洗浄し, ２次抗体にanti-rabbit抗体（GE Healthcare）を用いて室温で６０分間反応させた。ＴＢＳＴで５分間， ３回洗浄し， 発色剤（ECL plus, GE Healthcare）を４分間反応させた。画像解析装置（ImageQuant LAS 4000, GE Healthcare）を用いてバンドを検出し, 数値化した。その後, コントロール群に対する相対比を求めた。
(Measurement of PGC-1α activity)
The amount of PGC-1α in the muscle was measured by western-blotting. The flat muscles of the resting group were homogenized and the protein concentration was measured using the BCA method (BCA ™ Protein Assay Kit, Thermo SCIENTIFIC). The prepared protein sample was poured into a 10% gel (Wako), separated by electrophoresis, and transferred to a membrane using a transfer device (iBlot, Invitrogen). After blocking for 30 minutes (EzBlockChemi, ATTO CORPORATION), Tris buffered saline (BIO-RAD Laboratories) -Tween20 (Wako), washed 5 times with TBS-T for 5 minutes, and anti-PGC-1α antibody as the primary antibody ( CHEMICON International) for 60 minutes at room temperature. The plate was washed 3 times with TBST for 5 minutes, and reacted with the secondary antibody at room temperature for 60 minutes using an anti-rabbit antibody (GE Healthcare). The plate was washed 3 times with TBST for 5 minutes, and reacted with a color former (ECL plus, GE Healthcare) for 4 minutes. Bands were detected and digitized using an image analyzer (ImageQuant LAS 4000, GE Healthcare). Then, the relative ratio to the control group was obtained.
（ミトコンドリアＤＮＡの測定）
安静群の平目筋をＤＮＡ分離試薬（DNA zol BD Reagent, Invitrogen）でホモジナイズした後,ＤＮＡを抽出した。β−ａｃｔｉｎ（核ＤＮＡコード）とcytochrome oxidase II（ＣＯＸ−II）（ミトコンドリアＤＮAコード）をpolymerase chain reactionで増幅し, ＤＮＡコピー数を定量した。両者の比を用いてミトコンドリアＤＮＡ（ｍｔＤＮＡ）量を求めた。
(Measurement of mitochondrial DNA)
Rest the flat muscles of the rest group with DNA separation reagent (DNA zol DNA was extracted after homogenization with BD Reagent, Invitrogen. β-actin (nuclear DNA code) and cytochrome oxidase II (COX-II) (mitochondrial DNA code) were amplified by polymerase chain reaction, and the DNA copy number was quantified. The ratio of both was used to determine the amount of mitochondrial DNA (mtDNA).
以下の方法で、グルタチオンの運動機能性向上効果を測定した。
試験例１
飼育方法および実験プロトコール
実験動物には７週齢のＩＣＲ雄性マウス（清水実験材料）を用いて実験を行った。１週間の予備飼育後， 体重をもとにグルタチオン群（ｎ＝２１）と対照群（ｎ＝２１）の２群にわけた。グルタチオン（興人ライフサイエンス株式会社）を２．０％溶液に調整し， グルタチオン群に５μｌ／ｇ体重を１日１回，２週間経口投与した。対照群には蒸留水を同量，同期間経口投与した。飼育室は１２時間の明暗サイクルが保たれ，プラスティックゲージ内で水と飼料は自由に摂取できるものとした。
最終日にさらに対照安静群（ｎ＝１３）, 対照運動群（ｎ＝８），グルタチオン安静群（ｎ＝１３）およびグルタチオン運動群（ｎ＝８）の４群にわけた。運動群にはトレッドミル走運動を負荷し, その後, 全群解剖を行った。
The effect of improving glutathione's motor functionality was measured by the following method.
Test example 1
Breeding Method and Experimental Protocol Experiments were conducted using 7-week-old ICR male mice (Shimizu Experimental Materials) as experimental animals. After one week of preliminary breeding, the group was divided into two groups based on body weight: glutathione group (n = 21) and control group (n = 21). Glutathione (Kojin Life Science Co., Ltd.) was adjusted to a 2.0% solution, and 5 μl / g body weight was orally administered to the glutathione group once a day for 2 weeks. In the control group, the same amount of distilled water was orally administered during the same period. The breeding room maintained a 12-hour light-dark cycle, and water and feed could be freely consumed within the plastic gauge.
On the final day, it was further divided into 4 groups: a control rest group (n = 13), a control exercise group (n = 8), a glutathione rest group (n = 13), and a glutathione exercise group (n = 8). The exercise group was loaded with treadmill running, and then the whole group was dissected.
試験例２
運動および解剖プロトコール
運動負荷試験は, トレッドミル（ＭＫ６８０, 室町機械）を用いた。運動負荷実施日に, 安静群は運動負荷を行わず解剖し, 運動群には速度２５ｍ／分で３０分間のトレッドミル走運動を負荷し, 運動負荷終了直後に解剖を行った。麻酔下にて筋組織pHを測定した後, 両脚の平目筋を摘出した。筋肉はドライアイスで凍結後, 測定まで−８０℃で保存した。
Test example 2
Exercise and dissection protocol A treadmill (MK680, Muromachi Kikai) was used for the exercise load test. On the day of exercise, the rest group was dissected without any exercise load, the exercise group was subjected to a treadmill running exercise for 30 minutes at a speed of 25 m / min, and dissection was performed immediately after the end of the exercise load. The muscle tissue pH was measured under anesthesia, and then the flat muscles of both legs were removed. Muscles were stored at -80 ° C until measurement after freezing in dry ice.
筋組織pH
筋組織pHは, 安静時と比較して運動後で有意に低値を示した（ｐ < ０．００１）。また, 対照運動群と比較してグルタチオン運動群で有意に高値を示した（p < ０．０５）。（図１、図２）
比較として、ビタミンＣをグルタチオンと同様に投与したデータを取得した。
Muscle tissue pH
Muscle tissue pH was significantly lower after exercise than at rest (p <0.001). The glutathione exercise group was significantly higher than the control exercise group (p <0.05). (Fig. 1 and Fig. 2)
For comparison, data obtained by administering vitamin C in the same manner as glutathione was obtained.
骨格筋ＰＧＣ−１αおよびｍｔＤＮＡ
平目筋におけるＰＧＣ−１α発現量は対照群と比較してグルタチオン群で有意に高値を示した（p < ０．０５）。ｍｔＤＮＡ量（ＣＯＸ−ＩＩ／β−ａｃｔｉｎ）の相対比は、対照群と比較してグルタチオン群で有意に高値を示した（p < ０．０５）。（図３、図４）
比較としてビタミンＣのＰＧＣ−１αの発現量をグルタチオンと同条件でデータを取得した。
Skeletal muscle PGC-1α and mtDNA
The expression level of PGC-1α in the flat eye muscle was significantly higher in the glutathione group than in the control group (p <0.05). The relative ratio of mtDNA amount (COX-II / β-actin) was significantly higher in the glutathione group than in the control group (p <0.05). (Fig. 3, Fig. 4)
As a comparison, data were obtained under the same conditions as the glutathione expression level of vitamin C PGC-1α.
データはすべて平均値±標準誤差で示した。４群間の比較には二元配置分散分析を行った後, 多重比較検定（Bonferroni）を行った。２群間の比較にはStudentのｔ検定を行った。有意水準は５％とした。 All data are shown as mean ± standard error. For comparison between the four groups, a two-way analysis of variance was performed, followed by a multiple comparison test (Bonferroni). For comparison between the two groups, Student's t-test was performed. The significance level was 5%.
測定の結果、グルタチオンを投与した群については、筋組織pＨの低下が見られず、ＰＧＣ−１α発現量の増加、ｍｔＤＮＡ量の増加が見られた。このことから、グルタチオンを投与することで、運動機能の向上が確認された。一方、ビタミンＣでは、グルタチオンの効果が確認されなかった。 As a result of the measurement, in the group to which glutathione was administered, no decrease in muscle tissue pH was observed, but an increase in the expression level of PGC-1α and an increase in the amount of mtDNA were observed. From this, improvement of motor function was confirmed by administering glutathione. On the other hand, with vitamin C, the effect of glutathione was not confirmed.
以上より、グルタチオンを有効成分として含む、安全な運動機能性向上剤を提供することができる。また、ＰＧＣ−１αの活性化により、運動時だけでなく、安静時においても、筋肉組織中の代謝を活性化させ体内の脂肪代謝を促進するため、糖尿病などの生活習慣病を予防することも可能となる。 From the above, it is possible to provide a safe motor function improver containing glutathione as an active ingredient. In addition, activation of PGC-1α activates metabolism in muscle tissue not only during exercise but also at rest, and promotes fat metabolism in the body, thus preventing lifestyle-related diseases such as diabetes. It becomes possible.
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