The study of metabolic improvement by nutritional intervention controlling endogenous GIP (Mini Egg study): a randomized, cross-over study.

BACKGROUND: Given the major role of glucose-dependent insulinotropic polypeptide (GIP) in the regulation of adiposity, this study examined the effects induced by a diet based on the Japanese tradition (SMART WASHOKU) on the visceral fat area (VFA) and GIP secretions. METHODS: Overweight/obese men (n = 21; mean age, 41.0 ± 9.0 years; mean BMI, 25.2 ± 2.0 kg/m2) without diabetes were placed on either a SMART WASHOKU or control meal for 2 weeks, in a randomized, cross-over setup with a four-week washout period. RESULTS: For the meal tolerance test, blood samples were collected at 0, 30, 60, 120, 180, and 240 min post-meal, followed by measuring blood glucose, insulin, GIP, and glucagon-like peptide-1 (GLP-1) levels. Relative to a control meal, SMART WASHOKU meal yielded significantly lower plasma postprandial GIP concentrations (AUC: 700.0 ± 208.0 vs. 1117.0 ± 351.4 pmol/L・4 h, P < 0.05); however, between meals, there was no significant difference in the levels of GLP-1, peptide YY, and ghrelin. Compared to the control meal, SMART WASHOKU intervention significantly reduced VFA and the levels of LDL-cholesterol, triglyceride, and HbA1c after the chronic meal intervention. CONCLUSIONS: In conclusion, a SMART WASHOKU meal may decrease VFA and improve metabolic parameters in overweight/obese men, possibly via suppressing GIP secretion.

Increased plasma levels of glucose-dependent insulinotropic polypeptide are associated with decreased postprandial energy expenditure after modern Japanese meals.

PURPOSE: The nutritional changes that have accompanied the modernization of Japanese dietary patterns have led to significant increases in the number of people who are overweight or obese. This study aimed to clarify the effects of these nutritional changes on postprandial energy expenditure and the release of metabolism-regulating hormones. METHODS: The total daily energy content (20 % breakfast, 40 % lunch, and 40 % dinner) and macronutrient composition (carbohydrate/fat/protein) was 8807.3 kJ and 364.3:30.1:66.4 (g) for the traditional test diet and 9217.6 kJ and 331.7:66.1:76.9 (g) for the modern test diet. In experiment 1, nine healthy Japanese men participated in a crossover study during which they ingested a test diet comprising three meals; postprandial blood parameters were measured after each meal. In experiment 2, another ten men participated in a crossover study during which they ingested 2 meals, after which metabolic responses and blood variables were evaluated. RESULTS: The modern diet induced greater blood levels of glucose-dependent insulinotropic polypeptide (GIP) and ghrelin than did the traditional diet. The expected increase in postprandial energy expenditure (∆REE) tended to be dampened after the modern compared with the traditional diet. GIP was inversely correlated with ∆REE after lunch, and ghrelin was positively associated with ∆REE. CONCLUSION: Both GIP and ghrelin are robust indicators of postprandial energy expenditure. The nutritional changes accompanying the modernization of Japanese dietary patterns may increase the levels of the anabolic intestinal hormone GIP, which is associated with ∆REE, in the Japanese population. The contribution of an increased ghrelin concentration to the decreased ∆REE after the modern diet warrants further investigation.

Reduction in hydroxyhydroquinone from coffee increases postprandial fat utilization in healthy humans: a randomized double-blind, cross-over trial.

The present study aimed to clarify the effect of reduction in hydroxyhydroquinone (HHQ) from roasted coffee on energy utilization in humans. Indirect calorimetry showed that one-week ingestion of HHQ-reduced coffee led to significantly higher postprandial fat utilization than that of HHQ-containing coffee. This finding indicates that reduction in HHQ from coffee increases postprandial fat utilization.

Daily consumption of tea catechins improves aerobic capacity in healthy male adults: a randomized double-blind, placebo-controlled, crossover trial.

Our previous studies demonstrated that dietary supplementation with tea catechins combined with exercise improved endurance capacity in mice. This study aimed to demonstrate the effect of daily tea catechin consumption on aerobic capacity in humans. Sixteen Japanese non-athlete male subjects (aged 25-47 years) took 500 mL of a test beverage with or without tea catechins (570 mg) daily for 8 weeks and attended a training program twice a week. Aerobic capacity was evaluated by indirect calorimetry and near-infrared spectroscopy during graded cycle exercise. Catechin beverage consumption was associated with a significantly higher ventilation threshold during exercise and a higher recovery rate of oxygenated hemoglobin and myoglobin levels after graded cycle exercise when compared to subjects receiving the placebo beverage. These results indicate that daily consumption of tea catechins increases aerobic capacity when combined with semiweekly light exercise, which may be due to increased skeletal muscle aerobic capacity.

Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process.

Deletion of nuclear factor-κB p50 upregulates fatty acid utilization and contributes to an anti-obesity and high-endurance phenotype in mice.

The transcription factor nuclear factor-κB (NF-κB) plays an important role in regulating physiological processes such as immunity and inflammation. In addition to this primary role, NF-κB interacts physically with peroxisome proliferator-activated receptors regulating lipid metabolism-related gene expression and inhibits their transcriptional activity. Therefore, inhibition of NF-κB may promote fatty acid utilization, which could ameliorate obesity and improve endurance capacity. To test this hypothesis, we attempted to elucidate the energy metabolic status of mice lacking the p50 subunit of NF-κB (p50 KO mice) from the tissue to whole body level. p50 KO mice showed a significantly lower respiratory quotient throughout the day than did wild-type (WT) mice; this decrease was associated with increased fatty acid oxidation activity in liver and gastrocnemius muscle of p50 KO mice. p50 KO mice that were fed a high-fat diet were also resistant to fat accumulation and adipose tissue inflammation. Furthermore, p50 KO mice showed a significantly longer maximum running time compared with WT mice, with a lower respiratory exchange ratio during exercise as well as higher residual muscle glycogen content and lower blood lactate levels after exercise. These results suggest that p50 deletion facilitates fatty acid catabolism, leading to an anti-obesity and high-endurance phenotype of mice and supporting the idea that NF-κB is an important regulator of energy metabolism.

Green tea catechins enhance norepinephrine-induced lipolysis via a protein kinase A-dependent pathway in adipocytes.

Green tea catechins have been shown to attenuate obesity in animals and humans. The catechins activate adenosine monophosphate-activated protein kinase (AMPK), and thereby increase fatty acid oxidation in liver and skeletal muscles. Green tea catechins have also been shown to reduce body fat in humans. However, the effect of the catechins on lipolysis in adipose tissue has not been fully understood. The aim of this study was to clarify the effect of green tea catechins on lipolysis in adipocytes and to elucidate the underlying mechanism. Differentiated mouse adipocyte cell line (3T3-L1) was stimulated with green tea catechins in the presence or absence of norepinephrine. Glycerol and free fatty acids in the media were measured. Phosphorylation of hormone-sensitive lipase (HSL) was determined by Western blotting, and the mRNA expression levels of HSL, adipose triglyceride lipase (ATGL), and perilipin were determined by quantitative RT-PCR. The cells were treated with inhibitors of protein kinase A (PKA), protein kinase C (PKC), protein kinase G (PKG), or mitogen-activated protein kinase (MAPK) to determine the responsible pathway. Treatment of 3T3-L1 adipocytes with green tea catechins increased the level of glycerol and free fatty acids released into the media in the presence, but not absence, of norepinephrine, and increased the level of phosphorylated HSL in the cells. The catechins also increased mRNA and protein levels of HSL and ATGL. PKA inhibitor (H89) attenuated the catechin-induced increase in glycerol release and HSL phosphorylation. The results demonstrate that green tea catechins enhance lipolysis in the presence of norepinephrine via a PKA-dependent pathway in 3T3-L1 adipocytes, providing a potential mechanism by which green tea catechins could reduce body fat.

Dietary milk fat globule membrane supplementation combined with regular exercise improves skeletal muscle strength in healthy adults: a randomized double-blind, placebo-controlled, crossover trial.

BACKGROUND: Our previous studies demonstrated that dietary supplementation with milk fat globule membrane (MFGM) combined with habitual exercise improved muscle strength by stimulating neuromuscular development in mice. This study aimed to demonstrate the beneficial effects of dietary MFGM supplementation plus regular exercise on muscle strength and neuromuscular function in healthy humans. METHODS: The study was designed as a randomized, double-blind, placebo-controlled, crossover trial. Fourteen Japanese adults aged 31-48 years took daily MFGM (1 g) or placebo tablets during the 4-week study period and attended a training program twice a week. Physical function tests and surface electromyography (EMG) were conducted at baseline and at the end of the study period. RESULTS: The MFGM group had significantly greater leg extension strength than the placebo group after the 4-week study period. Surface EMG showed that the MFGM group had a significantly higher root mean square amplitude than the placebo group, which indicated that the MFGM group had higher motor unit activity. CONCLUSIONS: Dietary MFGM supplementation combined with regular exercise improves skeletal muscle strength, which may be due to increased motor unit recruitment in healthy Japanese middle-aged adults.

Dietary milk fat globule membrane improves endurance capacity in mice.

Milk fat globule membrane (MFGM) comprises carbohydrates, membrane-specific proteins, glycoproteins, phospholipids, and sphingolipids. We evaluated the effects of MFGM consumption over a 12-wk period on endurance capacity and energy metabolism in BALB/c mice. Long-term MFGM intake combined with regular exercise improved endurance capacity, as evidenced by swimming time until fatigue, in a dose-dependent manner. The effect of dietary MFGM plus exercise was accompanied by higher oxygen consumption and lower respiratory quotient, as determined by indirect calorimetry. MFGM intake combined with exercise increased plasma levels of free fatty acids after swimming. After chronic intake of MFGM combined with exercise, the triglyceride content in the gastrocnemius muscle increased significantly. Mice given MFGM combined with exercise had higher mRNA levels of peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc1α) and CPT-1b in the soleus muscle at rest, suggesting that increased lipid metabolism in skeletal muscle contributes, in part, to improved endurance capacity. MFGM treatment with cyclic equibiaxial stretch consisting of 10% elongation at 0.5 Hz with 1 h on and 5 h off increased the Pgc1α mRNA expression of differentiating C2C12 myoblasts in a dose-dependent manner. Supplementation with sphingomyelin increased endurance capacity in mice and Pgc1α mRNA expression in the soleus muscle in vivo and in differentiating myoblasts in vitro. These results indicate that dietary MFGM combined with exercise improves endurance performance via increased lipid metabolism and that sphingomyelin may be one of the components responsible for the beneficial effects of dietary MFGM.

Stimulation of postprandial fat utilization in healthy humans by daily consumption of chlorogenic acids.

Long-term ingestion of coffee polyphenols (chlorogenic acids, CGAs) reduces body fat in humans and rodents. While CGA supplementation has been shown to increase fat utilization in rodents, evidence in humans is still limited. The present study clarifies the effect of daily CGA consumption on energy metabolism in humans. Eighteen healthy male subjects (36.1 ± 7.4 y of age) participated in a placebo-controlled, double-blind, crossover, intervention study with two different test beverages. The subjects consumed 185 mL of a test beverage with or without CGAs (329 mg) daily for 4 wk. The energy metabolism was evaluated by using indirect calorimetry before and after the test period during fasting and up to 180 min postprandially. Indirect calorimetry showed that a 4-wk ingestion of the CGA beverage led to a significantly higher postprandial energy expenditure than that of the control beverage. The subjects ingesting the CGA beverage exhibited higher postprandial fat utilization than those consuming the control beverage. The daily CGA consumption therefore increased postprandial fat utilization in healthy humans.

Tyrosine Is a Booster of Leucine-Induced Muscle Anabolic Response.

Leucine (Leu), an essential amino acid, is known to stimulate protein synthesis in the skeletal muscle via mTOR complex 1 (mTORC1) activation. However, the intrinsic contribution of other amino acids to Leu-mediated activation of mTORC1 signaling remains unexplored. This study aimed to identify amino acids that can promote mTORC1 activity in combination with Leu and to assess the effectiveness of these combinations in vitro and in vivo. We found that tyrosine (Tyr) enhanced Leu-induced phosphorylation of S6 kinase (S6K), an indicator of mTORC1 activity, although it exerted no such effect individually. This booster effect was observed in C2C12 cells, isolated murine muscle, and the skeletal muscles of mice orally administered the amino acids. To explore the molecular mechanisms underlying this Tyr-mediated booster effect, the expression of the intracellular Leu sensors, Sestrin1 and 2, was suppressed, and the cells were treated with Leu and Tyr. This suppression enabled Tyr alone to induce S6K phosphorylation and enhanced the booster effect, suggesting that Tyr possibly contributes to mTORC1 activation when Sestrin-GAP activity toward Rags 2 (GATOR2) is dissociated through Sestrin knockdown or the binding of Sestrins to Leu. Collectively, these results indicate that Tyr is a key regulator of Leu-mediated protein synthesis.

Dietary 1-monoolein decreases postprandial GIP release by reducing jejunal transport of glucose and fatty acid in rodents.

Postprandial secretion of insulin and glucose-dependent insulinotropic polypeptide (GIP) is differentially regulated by not only dietary carbohydrate but also fat. Recent studies have shown that the ingestion of diacylglycerol (DAG) results in lower postprandial insulin and GIP release than that of triacylglycerol (TAG), suggesting a possible mechanism for the antiobesity effect of DAG. The structural and metabolic characteristics of DAG are believed to be responsible for its beneficial effects. This study was designed to clarify the effect of 1-monoacylglycerol [oleic acid-rich (1-MO)], the characteristic metabolite of DAG, on postprandial insulin and GIP secretion, and the underlying mechanism. Dietary 1-MO dose dependently stimulated whole body fat utilization, and reduced high-fat diet-induced body weight gain and visceral fat accumulation in mice, both of which are consistent with the physiological effect of dietary DAG. Although glucose-stimulated insulin and GIP release was augmented by the addition of fat, coingestion of 1-MO reduced the postprandial hormone release in a dose-dependent manner. Either glucose or fatty acid transport into the everted intestinal sacs and enteroendocrine HuTu-80 cells was also reduced by the addition of 1-MO. Reduction of either glucose or fatty acid transport or the nutrient-stimulated GIP release by 1-MO was nullified when the intestine was pretreated with sodium-glucose cotransporter-1 (SGLT-1) or fatty acid translocase (FAT)/CD36 inhibitor. We conclude that dietary 1-MO attenuates postprandial GIP and insulin secretion by reducing the intestinal transport of the GIP secretagogues, which may be mediated via SGLT-1 and FAT/CD36. Reduced secretion of these anabolic hormones by 1-MO may be related to the antiobesity effect of DAG.

Hydroxypropylated distarch phosphate versus unmodified tapioca starch: fat oxidation and endurance in C57BL/6J mice.

An RS4-type resistant starch is a chemically modified starch that shows reduced availability in comparison to the corresponding unmodified starch. Hydroxypropylated distarch phosphate (HDP) is an RS4-type resistant starch that increases energy expenditure and prevents high-fat diet-induced obesity through increased hepatic fatty acid oxidation. The aim of this study was to clarify the acute effects of HDP from tapioca starch (HPdTSP) on physical performance in mice. Male C57BL/6J mice were used to examine the effects of a single administration of 2 mg/g body weight HPdTSP or unmodified tapioca starch (TS) on postprandial responses in serum metabolic parameters, running endurance capacity on a treadmill, whole-body energy metabolism during exercise, activity of enzymes involved in fatty acid oxidation, liver and gastrocnemius muscle glycogen content, and serum glucose, insulin, non-esterified fatty acid, lactate, and triglyceride levels after exercise. Running time to fatigue was significantly greater in HPdTSP mice than in TS mice. Furthermore, HPdTSP maintained higher fat oxidation and this was associated with a greater activity of enzymes in fatty acid oxidation in the muscle during exercise. The blood lactate and serum insulin levels after exercise was significantly lower in HPdTSP mice than in TS mice. Liver glycogen was significantly higher in HPdTSP mice than in TS mice. These results suggest that acute oral administration of the RS4-type resistant starch, HPdTSP, maintained higher fat oxidation and reduced liver glycogen consumption during exercise and increased running endurance capacity in mice.

Regulation of postprandial blood metabolic variables by TEMPO-oxidized cellulose nanofibers.

Wood cellulose was converted to individual nanofibers of approximately 4 nm width and 380-570 nm average length by TEMPO-mediated oxidation. The TEMPO-oxidized cellulose nanofibers (TOCNs) were orally administered with glucose and glyceryl trioleate to mice and postprandial responses of blood glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), and triglycerides were studied. Both blood insulin and GIP concentrations were decreased by TOCN with a carboxyl content and aspect ratio of 1.2 mmol g(-1) and 120, respectively, in dose-dependent manners (0-0.3 mg g(-1) body weight). Of the TOCNs examined, that with a carboxyl content and aspect ratio of 1.2 mmol g(-1) and 120, respectively, was the most effective in reducing postprandial blood glucose, plasma insulin, GIP, and triglyceride concentrations. Thus, TOCNs were found to exhibit characteristic biological activities when administered to mice and may have potential applications in biomedical fields for human health.

Dietary supplementation with hydroxypropyl-distarch phosphate from waxy maize starch increases resting energy expenditure by lowering the postprandial glucose-dependent insulinotropic polypeptide response in human subjects.

The aim of the present study was to investigate the effects of hydroxypropyl-distarch phosphate (HDP) supplementation on postprandial energy metabolism and glucose-dependent insulinotropic polypeptide (GIP) in human subjects. A total of ten healthy male subjects, with a mean BMI of 23·6 (SEM 1·3) kg/m(2), age 35·2 (SEM 1·9) years and body weight 71·1 (SEM 4·0) kg, participated in a randomised, cross-over, intervention study with two different test meals (1673·6 kJ) containing either waxy maize starch or HDP from waxy maize starch (degree of substitution 0·154, P content 0·004 %). Resting energy expenditure (REE) and blood concentrations of various biomarkers were measured at fasting and up to 180 min postprandially. Indirect calorimetry showed that the HDP meal caused higher REE (P < 0·05) and fat utilisation (P < 0·001) than the waxy maize starch meal. The HDP meal led to significantly lower postprandial glucose (P < 0·05), insulin (P < 0·05) and GIP (P < 0·05) responses than the waxy maize starch meal. Both postprandial REE (R - 0·576, P < 0·01) and fat utilisation (R - 0·514, P < 0·05) were negatively correlated with the postprandial GIP response, but not with the glucose and insulin responses. In conclusion, dietary supplementation with HDP lowers postprandial GIP and increases postprandial REE and fat utilisation in healthy humans. An HDP-rich diet may therefore have beneficial implications in weight management. Further studies are required to confirm the efficacy in overweight or obese subjects, and to determine the precise mechanisms.

RS4-type resistant starch prevents high-fat diet-induced obesity via increased hepatic fatty acid oxidation and decreased postprandial GIP in C57BL/6J mice.

Chemically modified starches (CMS) are RS4-type resistant starch, which shows a reduced availability, as well as high-amylose corn starch (HACS, RS2 type), compared with the corresponding unmodified starch. Previous studies have shown that RS4 increases fecal excretion of bile acids and reduces zinc and iron absorption in rats. The aim of this study was to investigate the effects of dietary RS4 supplementation on the development of diet-induced obesity in mice. Weight- and age-matched male C57BL/6J mice were fed for 24 wk on a high-fat diet containing unmodified starch, hydroxypropylated distarch phosphate (RS4), or HACS (RS2). Those fed the RS4 diet had significantly lower body weight and visceral fat weight than those fed either unmodified starch or the RS2 diet. Those fed the RS4 diet for 4 wk had a significantly higher hepatic fatty acid oxidation capacity and related gene expression and lower blood insulin than those fed either unmodified starch or the RS2 diet. Indirect calorimetry showed that the RS4 group exhibited higher energy expenditure and fat utilization compared with the RS2 group. When gavaged with fat (trioleate), RS4 stimulated a lower postprandial glucose-dependent insulinotropic polypeptide (GIP; incretin) response than RS2. Higher blood GIP levels induced by chronic GIP administration reduced fat utilization in high-fat diet-fed mice. In conclusion, dietary supplementation with RS4-type resistant starch attenuates high-fat diet-induced obesity more effectively than RS2 in C57BL/6J mice, which may be attributable to lower postprandial GIP and increased fat catabolism in the liver.

Involvement of ammonia metabolism in the improvement of endurance performance by tea catechins in mice.

Blood ammonia increases during exercise, and it has been suggested that this increase is both a central and peripheral fatigue factor. Although green tea catechins (GTCs) are known to improve exercise endurance by enhancing lipid metabolism in skeletal muscle, little is known about the relationship between ammonia metabolism and the endurance-improving effect of GTCs. Here, we examined how ammonia affects endurance capacity and how GTCs affect ammonia metabolism in vivo in mice and how GTCs affect mouse skeletal muscle and liver in vitro. In mice, blood ammonia concentration was significantly negatively correlated with exercise endurance capacity, and hyperammonaemia was found to decrease whole-body fat expenditure and fatty acid oxidation-related gene expression in skeletal muscle. Repeated ingestion of GTCs combined with regular exercise training improved endurance capacity and the expression of urea cycle-related genes in liver. In C2C12 myotubes, hyperammonaemia suppressed mitochondrial respiration; however, pre-incubation with GTCs rescued this suppression. Together, our results demonstrate that hyperammonaemia decreases both mitochondrial respiration in myotubes and whole-body aerobic metabolism. Thus, GTC-mediated increases in ammonia metabolism in liver and resistance to ammonia-induced suppression of mitochondrial respiration in skeletal muscle may underlie the endurance-improving effect of GTCs.

Coffee polyphenols prevent cognitive dysfunction and suppress amyloid ß plaques in APP/PS2 transgenic mouse.

Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, evidence demonstrating the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer's disease is limited. The present study investigated the effect of chlorogenic acids on the prevention of cognitive dysfunction in APP/PS2 transgenic mouse model of Alzheimer's disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was determined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Immunohistochemical analysis revealed that chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid ß (Aß) plaques in the hippocampus. Furthermore, we determined that 5-caffeoylquinic acid, one of the primary coffee polyphenols, did not inhibit Aß fibrillation; however, degraded Aß fibrils. In conclusion, our results demonstrate that coffee polyphenols prevent cognitive deficits and reduce Aß plaque deposition via disaggregation of Aß in the APP/PS2 mouse.

DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice.

Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared with the controls, suggesting enhanced neuromuscular transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.

Continuous Supplementation of Milk Fat Globule Membrane with Habitual Exercise from a Young Age Improves Motor Coordination and Skeletal Muscle Function in Aged Mice.

Since the decline of physical performance gradually progresses with aging, continuous exercise with nutritional supplementation from a young age is a feasible and effective way to maintain a comfortable life until late old age. We examined the effects of continuous milk fat globule membrane (MFGM) supplementation combined with voluntary running exercise (VR) for prevention of aging-associated declines in physical performance in naturally aging mice. The MFGM with VR group showed a significantly attenuated age-related decline in motor coordination and suppression of the loss of muscle mass and strength. Compared with the control group, the MFGM with VR group showed significantly higher mRNA and protein expression for docking protein 7, which maintains neuromuscular junction (NMJ) integrity, in the quadriceps muscles. These results suggest that dietary MFGM and VR attenuate natural aging-related decline in motor coordination and muscle function by regulating NMJ integrity.