Use of tyrosol as creatine physiological effect enhancer and application in continuous high-intensity exercise

Abstract

Disclosed are a use of tyrosol as a creatine physiological effect enhancer and an application in continuous high-intensity exercise. The enhancement of physiological effects includes, but is not limited to, enhancement of muscle endurance, and reduction in the degree of decline in muscle strength; enhancement of muscle utilization of creatine; tyrosol stimulating the effect of creatine on improving endurance and reducing the degree of decline in endurance level; accelerating the resynthesis of phosphocreatine and increasing the level of phosphocreatine; and improving resistance performance and endurance exercise performance. In particular, muscle endurance after continuous high-intensity exercise will not decrease, or will not decrease significantly.

Description

Uses of tyrosol as a creatine physiological enhancer and its application in continuous high-intensity exercise. Technical Field

[0001] This invention relates to the field of sports nutrition supplements, and in particular to the application of tyrosol as an enhancer of the physiological effects of creatine and its application in continuous high-intensity exercise. Background Technology

[0002] Creatine, a nitrogenous organic acid, helps provide energy to muscle and nerve cells. It is commonly added to various sports supplements, primarily for storing creatine phosphate in muscle tissue. Under the action of creatine kinase, creatine can be converted into creatine phosphate in the body. When the body needs ATP, creatine phosphate can be rapidly mobilized and used to produce ATP under the action of creatine kinase. The level of creatine phosphate and its resynthetic capacity significantly affect the efficiency of muscle power output.

[0003] The ATP and creatine phosphate stored in muscles are the first energy sources mobilized during exercise, and are generally depleted within the first few seconds of muscle contraction. Subsequently, glycolysis or mitochondrial aerobic respiration becomes the primary energy source. Because of the instantaneous energy supply of creatine phosphate, it plays a crucial role in some explosive sports, such as weightlifting and sprinting. Many studies have confirmed that creatine supplementation can enhance strength and improve explosive performance; therefore, athletes and some sports enthusiasts now choose to supplement with creatine to increase creatine phosphate levels in the body to enhance the explosive power of muscle contraction. However, some studies have shown that creatine supplementation mainly increases strength and explosive power, but has no significant effect on improving endurance. Furthermore, due to the rapid depletion of creatine phosphate, even with long-term creatine supplementation, muscle strength still decreases significantly after resistance training and a short recovery period compared to the first exercise session. Moreover, continuous high-intensity exercise causes the muscle strength gains from creatine to disappear even faster. This indicates that creatine supplementation cannot sustain a high level of muscle strength during continuous exercise. In many sports competitions, and even in daily training, repeated exercises at short intervals are very common and necessary to achieve good athletic performance. Even so, creatine remains popular in the sports field, but other methods or substances are still needed to compensate for its shortcomings, especially for continuous high-intensity exercise performance. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of the prior art by providing tyrosol and / or tyrosol derivatives as a physiological enhancer of creatine and / or creatine derivatives.

[0005] Furthermore, tyrosol and / or tyrosol derivatives, including salts, esters, acids, ketones, polymers, cocrystals, chelates, complexes, glycosides, hydrates, and substances formed therefrom by non-chemical bonding with other substances. Tyrosol derivatives are digested or metabolized in the body to form tyrosol, or perform the same or similar physiological functions as tyrosol.

[0006] Furthermore, creatine and / or creatine derivatives, including creatine salts, esters, ketones, hydrates, polymers, cocrystals, chelates, complexes, glycosides, and substances formed therefrom by non-chemical bonding with other substances. Examples include creatine ethyl ester, creatine phosphate, guanidinoacetic acid, creatine citrate, zinc magnesium creatine, basic creatine, creatine pyruvate, hydrated creatine (including but not limited to creatine monohydrate), and creatine malate. Creatine derivatives are digested or metabolized in the body to form creatine, or perform the same or similar physiological functions as creatine.

[0007] Furthermore, tyrosol and / or tyrosol derivatives: 20 mg-3 g, creatine and / or creatine derivatives: 500 mg-10 g. Alternatively, the dosage of tyrosol derivatives may be calculated based on the molar amount of tyrosol, falling within 20 mg-3 g. "Tyrosol and tyrosol derivatives: 20 mg-3 g" should be understood as the total dosage of tyrosol and tyrosol derivatives being 20 mg-3 g; or the dosage of creatine derivatives may be calculated based on the molar amount of creatine, falling within 500 mg-10 g. "Crease and creatine derivatives: 500 mg-10 g" should be understood as the total dosage of creatine and creatine derivatives being 500 mg-10 g.

[0008] The enhanced physiological effects include, but are not limited to, increased muscle endurance and reduced muscle strength loss; enhanced muscle utilization of creatine; tyrosol stimulating the effect of creatine on endurance improvement and maintaining a reduced rate of endurance decline; accelerated resynthesis of phosphocreatine and increased phosphocreatine levels; and improved resistance and endurance performance. In particular, muscle endurance does not decrease or decreases significantly after continuous high-intensity exercise.

[0009] The present invention also provides a composition comprising tyrosol and / or tyrosol derivatives: 20 mg-3 g, and creatine and / or creatine derivatives: 500 mg-10 g.

[0010] Alternatively, the dosage of tyrosol derivatives can be calculated based on the molar amount of tyrosol, falling between 20 mg and 3 g. "Tyrosol and tyrosol derivatives: 20 mg - 3 g" should be understood as the total dosage of tyrosol and its derivatives being 20 mg - 3 g. Or, the dosage of creatine derivatives can be calculated based on the molar amount of creatine, falling between 500 mg and 10 g. "Crease and creatine derivatives: 500 mg - 10 g" should be understood as the total dosage of creatine and its derivatives being 500 mg - 10 g.

[0011] The products of the compositions described in this invention can be in various dosage forms, including but not limited to common pharmaceutical dosage forms such as powders, suppositories, gels, oral liquids, hard capsules, and soft capsules, as well as common dosage forms of health foods and dietary supplements such as beverages, solid beverages, soft drinks, hard capsules, soft capsules, multi-layer hard capsules, melt-in-your-mouth beans, freeze-dried powders, milk beans, chocolate, gummies, filled gummies, filled chocolates, tea beverages, and cold brew coffee.

[0012] This invention also provides tyrosol and / or tyrosol derivatives for use as physiological enhancers of creatine and / or creatine derivatives during continuous high-intensity exercise. Further, the tyrosol and / or tyrosol derivatives include tyrosol salts, esters, acids, ketones, polymers, cocrystals, chelates, complexes, glycosides, hydrates, and substances formed therefrom by non-chemical bonding with other substances. The tyrosol derivatives are digested or metabolized in the body to form tyrosol, or exert physiological effects similar to or comparable to tyrosol.

[0013] Furthermore, creatine and / or creatine derivatives, including creatine salts, esters, ketones, hydrates, polymers, cocrystals, chelates, complexes, glycosides, and substances formed therefrom by non-chemical bonding with other substances. Examples include creatine ethyl ester, creatine phosphate, guanidinoacetic acid, creatine citrate, zinc magnesium creatine, basic creatine, creatine pyruvate, hydrated creatine (including but not limited to creatine monohydrate), and creatine malate. Creatine derivatives are digested or metabolized in the body to form creatine, or perform the same or similar physiological functions as creatine.

[0014] Furthermore, tyrosol and / or tyrosol derivatives: 20 mg-3 g, creatine and / or creatine derivatives: 500 mg-10 g. Alternatively, the dosage of tyrosol derivatives may be calculated based on the molar amount of tyrosol, falling within 20 mg-3 g. "Tyrosol and tyrosol derivatives: 20 mg-3 g" should be understood as the total dosage of tyrosol and tyrosol derivatives being 20 mg-3 g; or the dosage of creatine derivatives may be calculated based on the molar amount of creatine, falling within 500 mg-10 g. "Crease and creatine derivatives: 500 mg-10 g" should be understood as the total dosage of creatine and creatine derivatives being 500 mg-10 g.

[0015] Furthermore, continuous high-intensity exercise refers to high-intensity exercise performed multiple times with intervals of 1 hour, 5 hours, 10 hours, 1 day, 2 days, 3 days, etc., such as 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, etc.

[0016] The enhanced physiological effects include, but are not limited to, increased muscle endurance and reduced muscle strength loss; enhanced muscle utilization of creatine; tyrosol stimulating the effect of creatine on endurance improvement and maintaining a reduced rate of endurance decline; accelerated resynthesis of phosphocreatine and increased phosphocreatine levels; and improved resistance and endurance performance. In particular, muscle endurance does not decrease or decreases significantly after continuous high-intensity exercise. Attached Figure Description

[0017] Figure 1 shows the trend of grip strength changes in mice in Experiment Example 2;

[0018] Figure 2 shows the trend of exhaustive swimming time for mice in each group in Experiment 2;

[0019] Figure 3 shows the trend of grip strength changes in mice in each group of the experimental case;

[0020] Figure 4. The trend of grip strength changes in mice in each group with low doses of tyrosol in the experimental case;

[0021] Figure 5 shows the trend of exhaustive swimming time for mice in each group;

[0022] Figure 6 shows the trend of exhaustive swimming time in mice of different groups with low doses of tyrosol in the experimental case. Detailed Implementation

[0023] To facilitate understanding by those skilled in the art, the present invention will be further described below with reference to embodiments. The content mentioned in the embodiments is not intended to limit the present invention. Example 1

[0024] Application of tyrosol as a physiological enhancer of creatine.

[0025] Tyrosol and / or tyrosol derivatives: 20 mg, creatine and / or creatine derivatives: 10 g. Example 2

[0026] Application of tyrosol as a physiological enhancer of creatine.

[0027] Tyrosol and / or tyrosol derivatives: 3g, creatine and / or creatine derivatives: 500mg. Example 3

[0028] Application of tyrosol as a physiological enhancer of creatine.

[0029] Tyrosol and / or tyrosol derivatives: 1g, creatine and / or creatine derivatives: 2g. Example 4

[0030] The application of tyrosol as a physiological enhancer of creatine in continuous high-intensity exercise.

[0031] Tyrosol and / or tyrosol derivatives: 20 mg, creatine and / or creatine derivatives: 10 g. Example 5

[0032] The application of tyrosol as a physiological enhancer of creatine in continuous high-intensity exercise.

[0033] Tyrosol and / or tyrosol derivatives: 3g, creatine and / or creatine derivatives: 500mg. Example 6

[0034] The application of tyrosol as a physiological enhancer of creatine in continuous high-intensity exercise.

[0035] Tyrosol and / or tyrosol derivatives: 1g, creatine and / or creatine derivatives: 2g. Example 7

[0036] The application of tyrosol as a physiological enhancer of creatine in continuous high-intensity exercise.

[0037] Tyrosol and / or tyrosol derivatives: 1g, creatine and / or creatine derivatives: 2g. Continuous high-intensity exercise is defined as high-intensity exercise performed every other day.

[0038] Experimental Example 1: Tyrosol Enhances Creatine Utilization

[0039] Animal Experiment: Thirty 8-week-old mice were prepared and, after one week of acclimatization to the laboratory environment, were randomly divided into three groups. Control group: normal diet without any added active ingredients; CR group: normal diet with 5% creatine monohydrate added; Ty+CR group: normal diet with 1% tyrosol and 5% creatine monohydrate added. After two weeks of feeding, the mice were anesthetized, and the leg skeletal muscles were dissected, revealing a bloodless surface and clearly visible connective tissue. Before the muscle contraction test, the muscles were incubated in a specific physiological buffer for 10 minutes to allow recovery from the dissection. The muscles were then clamped with aluminum clamps, and stimulation was performed using platinum electrodes and capacitors with alternating polarity discharges. The muscles were stimulated for 250 ms at six consecutive intervals, with each interval gradually decreasing from 4 s to 1 s. After each six-interval stimulation, the muscles were observed for one minute before the next round, for a total of four rounds. The muscles of the left and right legs of each group of mice were numbered, and the above-described electrical stimulation test was performed separately. Immediately after the electrical stimulation test, the levels of phosphocreatine (PCr) and creatine (CR) in the anatomical muscles of the right leg of all groups of mice were measured. The levels of phosphocreatine and creatine in the anatomical muscles of the left leg of all groups of mice were measured 5 minutes after the end of the test. The total creatine (TCr) level was the sum of the phosphocreatine and creatine levels. Standard fluorescence assays were used to determine the levels of phosphocreatine and creatine in muscle samples extracted after perchloric acid precipitation.

[0040] Table 1. Changes in phosphocreatine, creatine, and total creatine levels in skeletal muscle of mice in each group after continuous interval stimulation.

[0041]

[0042] Note: Values ​​are average ± SE, expressed in mmol / kg dry weight.

[0043] The data in Table 1 show that, whether measured immediately after stimulation or 5 minutes later, the levels of creatine, phosphocreatine, and total creatine in the CR and Ty+CR groups were higher than those in the control group. This indicates that pre-feeding with creatine monohydrate, creatine monohydrate, and tyrosol significantly increases the levels of creatine and phosphocreatine in mouse skeletal muscle. Furthermore, the Ty+CR group showed higher levels in all three indicators than the CR group, suggesting that supplementing with creatine and tyrosol together further increases creatine and phosphocreatine levels, making it more beneficial for muscle energy supply. The data in the table also show that the total creatine level in each group remained almost unchanged whether measured immediately after stimulation or 5 minutes later. However, the creatine level in each group decreased significantly after 5 minutes of recovery, while the phosphocreatine level increased significantly. This indicates that during electrical stimulation and muscle contraction, the muscles consume a large amount of phosphocreatine. After muscle contraction, the stored creatine rapidly converts into phosphocreatine to restore phosphocreatine reserves. Since the "pool" is limited (total creatine level remains unchanged), the key to enhancing phosphocreatine energy supply is to accelerate creatine conversion and enhance creatine utilization. By comparing the data from "immediate detection" and "detection after 5 minutes" within the three groups, we were surprised to find that 5 minutes after the end of the muscle contraction following electrical stimulation, the creatine levels in the three groups decreased by 50.12% in the control group, 53.86% in the CR group, and 54.3% in the Ty+CR group. This indicates that the Ty+CR group had the highest creatine conversion rate, suggesting that the addition of tyrosol enhanced the utilization of creatine in the body.

[0044] Experimental Example 2

[0045] Tyrosol maintains the high levels of muscle strength provided by creatine.

[0046] Animal Experiment 1: Six-week-old mice were used. After the first week of acclimatization, they were randomly divided into the following groups: Control group: normal diet, serving as the control group; Ty group: normal diet, administered 75 mg / kg tyrosol daily by gavage; CR group: normal diet, administered 260 mg / kg creatine monohydrate daily by gavage; Ty+CR group: normal diet, administered 75 mg / kg tyrosol + 260 mg / kg creatine monohydrate daily by gavage. This continued for 4 weeks. The first grip strength test was conducted 30 minutes after the last gavage. A grip strength meter was used to measure the grip strength of the mice's limbs. After resting for 1 hour, the mice underwent their first exhaustive swimming exercise. A 5% weight of tin wire and a detector were wrapped around the mouse's tail, and the mouse was placed in a weighted swimming tank at a water temperature of 30±1 ℃ for the exhaustive swimming test. Exhaustion was defined as three consecutive times the mouse touched the bottom within 30 seconds during the swim. Therefore, the detector detected the mouse's bottoming out. After the mouse was determined to be exhausted, the swimming tank automatically lifted the mouse's lane, and the exhaustive swimming time was recorded. Twenty-four hours after the first swimming exercise, a second grip strength test and exhaustive swimming exercise were performed using the same method as described above, and the grip strength data and exhaustive swimming time were recorded. Similarly, the third and fourth grip strength tests and exhaustive swimming exercises were performed 24 hours after the previous exercise, and the grip strength data and exhaustive swimming time were recorded. During the intervals, the gavage administration for each group remained unchanged.

[0047] In Figure 1, * indicates a significant difference compared to the control group, & indicates a significant difference compared to the creatine and tyrosine groups, and ns indicates no significant difference compared to the control group.

[0048] As shown in Figure 1, the muscle strength (grip strength) of mice in the creatine group (CR) and the tyrosol + creatine group (Ty + CR) was significantly improved compared to the control group, while the tyrosol group (Ty) did not show a significant improvement in muscle strength (the first grip strength data was not significantly different from the control group). In subsequent exercise sessions, the muscle strength of mice in the control group decreased sharply and rapidly, and the rate of decline in the creatine group was also as rapid as expected. However, we were surprised to find that the muscle strength of mice in the tyrosol + creatine group remained steadily at the initial high level during continuous high-intensity exercise, with almost no decline, and was always significantly higher than that of the control group. Moreover, starting from the second exercise, due to the rapid decline in muscle strength in the creatine group, a significant difference in grip strength values ​​began to appear between the two groups. Even though tyrosol supplementation did not significantly improve the muscle strength of mice, and despite the rapid consumption of creatine itself, the simultaneous supplementation of both brought unexpected results, namely, a powerful reversal of the decline in muscle strength in mice. This indicates that tyrosol can maintain the muscle strength-enhancing effect of creatine during continuous exercise, that is, maintain the effect of creatine on improving resistance exercise performance. This may be because tyrosol can promote the body's utilization of creatine and accelerate the resynthesis of phosphocreatine, consistent with Experimental Example 1.

[0049] Figure 2* indicates a significant difference compared to the control group, & indicates a significant difference compared to the creatine group, and ns indicates no significant difference compared to the control group.

[0050] As shown in Figure 2, the exercise time of mice in the tyrosol group and the tyrosol + creatine group was significantly longer than that of mice in the control group. The creatine group did not initially improve the mice's endurance (the first exercise time was not significantly different from the control group); the significant difference between the two groups only appeared afterward because the exercise time of the control group decreased significantly. The endurance improvement in the tyrosol + creatine group remained consistently high. Surprisingly, during continuous exercise, the exercise time of the other three groups decreased to varying degrees, while the decrease in exercise time of the tyrosol + creatine group was extremely slow and negligible, consistent with the trend observed in the grip strength test. This indicates that tyrosol stimulates the endurance-enhancing effect of creatine, and that simultaneous supplementation with tyrosol and creatine can maintain not only high levels of resistance exercise performance during continuous exercise but also high levels of endurance exercise performance.

[0051] Table 2. Percentage change in muscle strength in mice during and after continuous high-intensity exercise

[0052]

[0053] Note: The data is obtained by comparing the grip strength data of each group in the first exercise to reflect the change in grip strength between each exercise and the initial grip strength.

[0054] As can be seen from the data in Table 2, the grip strength of mice in each group was the highest during the first exercise. The muscle strength of mice in the control group, tyrosol group and creatine group decreased to varying degrees during the subsequent exercise. However, the muscle strength of mice in the tyrosol + creatine group hardly decreased. During continuous high-intensity exercise, the muscle strength level was always maintained at more than 97% of the high level of muscle strength before exercise.

[0055] Table 3. Percentage change in exhaustive exercise time in mice during and after continuous high-intensity exercise

[0056]

[0057] Note: The data is obtained by comparing the grip strength data of each group in the first exercise to reflect the change in the difference between the time to exhaustion and the time to exhaustion at the beginning of each exercise.

[0058] As shown in Table 3, the exercise time of mice in each group was highest during the first exercise session. The exercise time of mice in the control group, tyrosol group, and creatine group decreased to varying degrees in subsequent exercises. However, the endurance of mice in the tyrosol + creatine group hardly decreased, and their endurance performance remained above 96% of the high-level endurance performance of the first swimming exercise during continuous high-intensity exercise.

[0059] Experimental Example 3

[0060] Tyrosol maintains the high level of muscle strength induced by creatine – Animal Experiment 2: Six-week-old mice were randomly divided into the following groups after the first week of acclimatization: Control group: normal diet, serving as the control group; Ty 1 group: normal diet, administered 2.6 mg / kg daily by gavage; CR 1-3 groups: normal diet, administered 65 mg / kg, 390 mg / kg, and 1300 mg / kg creatine monohydrate daily by gavage; Ty+CR 1-4 groups: normal diet, administered 2.6 mg / kg tyrosol + 65 mg / kg creatine monohydrate, 130 mg / kg + 130 mg / kg, 390 mg / kg + 1300 mg / kg, and 2.6 mg / kg + 1300 mg / kg daily by gavage. Except for Ty 1, CR 1, and Ty+CR 1, which were fed continuously for 8 weeks, they were administered once daily by gavage, while the other groups were fed continuously for 4 weeks. CR 3, Ty+CR 3, and Ty+CR 4 received their daily doses via gavage twice daily. The control group was fed half until 4 weeks and the other half until 8 weeks. The first grip strength test was performed 30 minutes after the last gavage. One hour after the last gavage, the first exhaustive swimming exercise was performed, with the grip strength test and swimming exercise methods as above. 24 hours after the first swimming exercise, the second grip strength test and exhaustive swimming exercise were performed using the same method as above, and the grip strength data and exhaustive swimming time were recorded. Similarly, the third and fourth grip strength tests and exhaustive swimming exercises were performed 24 hours after the last exhaustive swimming exercise, and the grip strength data and exhaustive swimming time were recorded. The CR 3 and Ty+CR 4 groups underwent the eighth grip strength test and exhaustive swimming exercise, with the exercise methods remaining consistent with the above. The gavage administration for each group remained unchanged during the intervals.

[0061] Figure 3* indicates a significant difference compared to the control group, and & indicates a significant difference compared to the creatine group;

[0062] As shown in Figure 3, the muscle strength of mice in the creatine group and the two tyrosol + creatine groups was significantly higher than that of the control group. Similar to the results of the previous experiments, the muscle strength of mice in the two tyrosol + creatine groups remained almost unchanged during continuous exercise. Furthermore, we were surprised to find that even though the creatine dose in the tyrosol + creatine group (Ty+CR 2) was one-third that of the creatine group (CR 2), supplementing with the same proportion of tyrosol, the muscle strength of mice in the Ty+CR 2 group remained at the level of the initial grip strength, and the grip strength values ​​in the third and fourth attempts were significantly higher than those in the CR 2 group, due to the significant decrease in muscle strength in the CR 2 group. In the other tyrosol + creatine group (Ty+CR 3), both the tyrosol and creatine doses were increased, therefore this group had the highest grip strength from the beginning and continued to follow the above trend, maintaining the initial high level of muscle strength during continuous exercise.

[0063] In Figure 4, * indicates a significant difference compared to the control group, & indicates a significant difference compared to the creatine and tyrosine groups, and ns indicates no significant difference compared to the control group.

[0064] As shown in Figure 4, both the low-dose creatine group (CR 1) and the low-dose tyrosol + creatine group (Ty + CR 1) significantly improved muscle strength in mice, although the increase was not significant. The tyrosol + creatine group continued the aforementioned trend, maintaining a high level of muscle strength in mice during continuous exercise.

[0065] In Figure 5, * indicates a significant difference compared to the control group, # indicates a significant difference compared to the creatine group, and & indicates a significant difference compared to the Ty+CR 2 group.

[0066] As shown in Figure 5, while the high-dose creatine group (CR 2) enhanced exercise endurance and prolonged exercise time in mice, its effect was not as strong as that of CR 2 in grip strength testing. However, the group supplemented with the same proportion of tyrosol + creatine (Ty + CR 2) showed significantly higher exercise endurance than the high-dose CR 2 group, indicating that tyrosol compensated for the relatively weak endurance enhancement provided by creatine. Furthermore, the higher the dose (Ty + CR 3), the greater the endurance enhancement.

[0067] In Figure 6, * indicates a significant difference compared to the control group, & indicates a significant difference compared to the creatine and tyrosine groups, and ns indicates no significant difference compared to the control group.

[0068] As shown in Figure 6, the low-dose creatine group (CR 1) did not improve the exercise endurance of mice, and showed no significant difference from the control group throughout the continuous exercise, further highlighting the deficiency of creatine in improving endurance. However, the simultaneous supplementation with a small dose of tyrosol significantly improved the endurance of mice (Ty+CR 1), and the improvement was greater than that of the tyrosol-only group (Ty 1). The exercise time of Ty+CR 1 was significantly longer than that of Ty 1 (Ty+CR 1 was significantly different from Ty 1). This indicates that the presence of tyrosol stimulated the endurance-enhancing effect of creatine. Even though low-dose creatine cannot improve endurance, the combination of the two showed unexpected results, with the combination significantly improving endurance more than tyrosol alone.

[0069] In the comparison of CR 3 (1300 mg / kg creatine) and Ty+CR 4 (2.6 mg / kg tyrosol + 1300 mg / kg creatine) results, it was found that in the mouse grip strength test, the grip strength data of the two groups were almost the same from the first to the sixth repetition, with no significant difference. Both groups showed a decrease in muscle strength with increasing repetitions, which may be due to the dominant dosage of creatine in the composition, resulting in no difference between the composition group and the creatine group in the first six repetitions. However, unexpectedly, in the subsequent seventh and eighth repetitions, the grip strength value of the composition group was significantly higher than that of the creatine group. Although the muscle strength of both groups was still decreasing, the decrease in muscle strength of the composition group was slower, thus widening the gap with the creatine group. This indicates that the small amount of tyrosol in the composition still played a role in maintaining the muscle strength improvement brought by creatine during long-term continuous exercise, reducing the decline in muscle strength.

[0070] After four consecutive intermittent grip strength tests and exhaustive exercise, the first exercise test showed that the muscle strength of mice supplemented with tyrosol alone did not increase, while the muscle strength of mice supplemented with creatine, as well as those supplemented with both tyrosol and creatine, increased significantly as expected. However, in the second, third, and fourth consecutive high-intensity exercise tests, we surprisingly found that the muscle strength of the normal control group, the tyrosol group, and the creatine group all decreased significantly, with the decrease becoming increasingly larger. However, the muscle strength of mice supplemented with both tyrosol and creatine remained almost unchanged from the initial level, indicating that tyrosol and creatine had a synergistic effect in improving and maintaining muscle strength. Furthermore, the exhaustive exercise time showed the same trend, and the exercise time of mice supplemented with both tyrosol and creatine was significantly longer than that of the creatine group from the very first test. This suggests that tyrosol not only maintained the performance of creatine during continuous exercise but also significantly compensated for creatine's slightly less effective endurance enhancement.

[0071] The above experimental results indicate that combined tyrosol supplementation can enhance cellular utilization of creatine and increase the resynthesis of phosphocreatine. Although tyrosol supplementation alone does not increase muscle strength, the addition of tyrosol allows creatine to maintain a high level of muscle strength during exercise, reversing the reduction in muscle strength caused by high-intensity exercise. This suggests a synergistic effect between tyrosol and creatine. Furthermore, the addition of tyrosol also stimulates the endurance-enhancing effect of creatine. Combined supplementation of creatine and tyrosol not only enhances endurance performance but also improves resistance performance.

[0072] US Patent 9446006B2 discloses hydroxytyrosol or olive juice containing hydroxytyrosol in combination with at least one of the following compounds: creatine, coenzyme Q10, resveratrol, caffeine, L-carnitine, B vitamins (B1, B2, B3, B5, B6, and / or B12), and ginseng (preferably root) extract. It can be used to maintain or increase mitochondrial biogeneration in cardiac, skeletal, and liver tissues. The invention proposes that these compositions synergistically enhance the body's own ability to generate energy and / or enhance cellular energy production. It also relates to pharmaceutical and nutritional health compositions applicable to conditions characterized by alterations in mitochondrial function and biogeneration, such as heart strength, various liver diseases, improved muscle / fat ratio, and muscle endurance. The specification states that the benefits of the compositions include at least one of the following (the first four are extracted here): helping to improve endurance, promoting post-exercise recovery, reducing muscle fatigue, reducing muscle soreness, etc. In this patent, hydroxytyrosol is cited as a component with positive cardiovascular health protection and anti-atherosclerotic effects; subsequent examples show that hydroxytyrosol can promote mitochondrial function. The patent mentions creatine primarily to leverage its energy-enhancing properties. To produce more ATP and make it usable by the body (for strength, endurance, and muscle power), creatine transports energy generated in the form of ATP to muscle fibers in a usable form (creatine phosphate). Unlike our invention, this patent mainly focuses on selecting compositions based on enhancing mitochondrial function. The data shown in the examples also investigate the promoting effects of hydroxytyrosol and its combinations with other ingredients (caffeine and L-carnitine only) on mitochondrial activity and biogenesis, as well as their synergistic effects on mitochondrial energy production. The specification does not mention the role of hydroxytyrosol or tyrosol in maintaining muscle strength during continuous exercise, nor does it suggest that hydroxytyrosol or tyrosol can stimulate the endurance-enhancing effects of creatine, nor does it suggest that hydroxytyrosol or tyrosol can enhance the body's or cells' conversion and utilization of creatine. Our invention primarily explores the deeper synergistic effect of tyrosol and creatine. This patent, however, utilizes the characteristic of creatine to promote ATP production, proposing that the combination of hydroxytyrosol and creatine may enhance mitochondrial function and synergistically promote energy production, thereby generating a series of exercise benefits based on improved mitochondrial function. This is only a rough summary and lacks specific research data to support it. We believe that the technical effects of this invention cannot be expected.

[0073] Referring to the "Table of Equivalent Dose Ratios Based on Body Surface Area Between Humans and Animals" in *Pharmacological Experimental Methodology*, the daily human doses corresponding to the dosages of each substance used in the mouse experiments are calculated as follows:

[0074] Table 4. Equivalent doses for mice and humans

[0075]

[0076] It will be understood by those skilled in the art that, unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should also be understood that terms such as those defined in general dictionaries should be understood to have the same meaning as in the context of the prior art, and should not be interpreted in an idealized or overly formal sense unless specifically defined as herein.

[0077] It should be understood that the above detailed description of the technical solutions of the present invention with reference to preferred embodiments is illustrative and not restrictive. Those skilled in the art can modify the technical solutions described in the embodiments or make equivalent substitutions for some of the technical features based on reading this specification; however, these modifications or substitutions do not cause the essence of the corresponding technical solutions to depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The use of tyrosol and / or tyrosol derivatives as a physiological enhancer of creatine and / or creatine derivatives.

2. The application according to claim 1, characterized in that, Tyrosol and / or tyrosol derivatives, including salts, esters, acids, ketones, polymers, cocrystals, chelates, complexes, glycosides, hydrates, and substances formed therefrom by non-chemical bonding with other substances. and / or Creatine and / or creatine derivatives, including salts, esters, ketones, hydrates, polymers, cocrystals, chelates, complexes, glycosides, and substances formed therefrom by non-chemical bonding with other substances.

3. The application according to claim 1, characterized in that, Tyrosol and / or tyrosol derivatives: 20mg-3g, creatine and / or creatine derivatives: 500mg-10g; or the dosage of tyrosol derivatives is 20mg-3g of tyrosol based on molar amount; or the dosage of creatine derivatives is 500mg-10g of creatine based on molar amount.

4. The application according to claim 1, characterized in that, The enhanced physiological effects include, but are not limited to, increased muscle endurance and reduced muscle strength loss; enhanced muscle utilization of creatine; tyrosol stimulating the effect of creatine on endurance improvement and maintaining a reduced rate of endurance decline; accelerated resynthesis of phosphocreatine and increased phosphocreatine levels; and improved resistance and endurance performance. In particular, muscle endurance does not decrease or does not decrease significantly after continuous high-intensity exercise.

5. A composition, characterized in that, Including tyrosol and / or tyrosol derivatives: 20mg-3g, creatine and / or creatine derivatives: 500mg-10g; Alternatively, the dosage of tyrosol derivatives may be calculated based on the amount of tyrosol, ranging from 20mg to 3g; or the dosage of creatine derivatives may be calculated based on the amount of creatine, ranging from 500mg to 10g.

6. Tyrosol and / or tyrosol derivatives, as physiological enhancers of creatine and / or creatine derivatives in continuous high-intensity exercise.

7. The application according to claim 6, characterized in that, Tyrosol and / or tyrosol derivatives, including salts, esters, acids, ketones, polymers, cocrystals, chelates, complexes, glycosides, hydrates, and substances formed therefrom by non-chemical bonding with other substances. and / or Creatine and / or creatine derivatives, including salts, esters, ketones, hydrates, polymers, cocrystals, chelates, complexes, glycosides, and substances formed therefrom by non-chemical bonding with other substances.

8. The application according to claim 6, characterized in that, Tyrosol and / or tyrosol derivatives: 20mg-3g, creatine and / or creatine derivatives: 500mg-10g. Alternatively, the dosage of tyrosol derivatives may be 20mg-3g based on the molar amount of tyrosol; or the dosage of creatine derivatives may be 500mg-10g based on the molar amount of creatine.

9. The application according to claim 6, characterized in that, Continuous high-intensity exercise refers to high-intensity exercise performed multiple times with intervals of 1 hour, 5 hours, 10 hours, 1 day, 2 days, 3 days, etc., such as 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, etc.

10. The application according to claim 6, characterized in that, The enhanced physiological effects include increased muscle endurance and reduced muscle strength loss; enhanced muscle utilization of creatine; tyrosol stimulating the effect of creatine on endurance improvement and maintaining a reduced rate of endurance decline; accelerated resynthesis of phosphocreatine and increased phosphocreatine levels; and improved resistance and endurance performance. In particular, muscle endurance does not decrease or does not decrease significantly after continuous high-intensity exercise.

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