Medium-chain triglycerides (8:0 and 10:0) increase muscle mass and function in frail older adults: a combined data analysis of clinical trials.

Background: Three clinical trials have examined the chronic effects of medium-chain triglycerides (MCTs) on muscle mass and function in frail older adults (mean age 85 years old). However, significant increases in muscle mass and some muscle function relative to long-chain triglycerides (LCTs) have yet to be shown, possibly due to the small number of participants in each trial. Objective: We re-analyzed these previous clinical trials to clarify whether MCT supplementation can increase muscle mass and function. Analysis: After adding post hoc tests to the original report, we compared changes in measurement between the MCT and LCT groups in the first 2 trials and conducted a combined data analysis. Methods: In a combined data analysis, changes from baseline in measurements at the 3 months intervention in the MCTs- and LCTs-containing groups were assessed by analysis of covariance adjusted for baseline values of each measurement, age, sex, BMI, allocation to trial, habitual intakes in energy, protein, leucine, octanoic acid, decanoic acid, and vitamin D during the baseline period. The Mann-Whitney U test was used to analyze data on right and left knee extension times. Results: MCT supplementation for 3 months increased muscle function relative to LCT supplementation with and without an L-leucine (1.2 g) and vitamin D (cholecalciferol, 20 µg)-enriched supplement. In a combined data analysis (n = 29 in MCTs, n = 27 in LCTs), relative to supplementation with 6 g LCTs/day, supplementation with 6 g MCTs/day at dinner for 3 months significantly increased body weight (adjusted mean change from baseline: MCTs 1.2 vs. LCTs 0.2 kg, p = 0.023), right arm muscle area (MCTs 1.4 vs. LCTs-0.7 cm2, p = 0.002), left calf circumference (p = 0.015), right-hand grip strength (MCTs 1.6 vs. LCTs 0.3 kg, p = 0.017), right knee extension time (p = 0.021), left knee extension time (p = 0.034), walking speed (p = 0.002), and number of iterations in leg open and close test (p < 0.001) and decreased right triceps skinfold thickness (p = 0.016). Conclusion: In frail older adults, supplementation for 3 months with a low dose (6 g/day) of MCTs (C8:0 and C10:0) increased muscle mass and function. These findings indicate the potential for the practical use of MCTs in daily life in treating sarcopenia.

Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy, including FoxO1 and its targets.

Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.

Medium-Chain Triglycerides (8:0 and 10:0) Increase Mini-Mental State Examination (MMSE) Score in Frail Elderly Adults in a Randomized Controlled Trial.

BACKGROUND: Supplementation with medium-chain triglycerides (MCTs) was previously shown to increase muscle function in frail elderly individuals. OBJECTIVE: We aimed to assess effects of MCTs on cognition in such individuals. METHODS: We enrolled 64 elderly nursing home residents (85.5 ± 6.8 y; 13 men, 51 women; BMI 18.6 ± 2.5 kg/m2) in a 3-mo randomized, controlled, single-blinded, intervention trial. Participants were randomly allocated to 3 groups: the first group received supplemental L-leucine (1.2 g) and cholecalciferol (20 µg) enriched with 6 g/d of MCTs (LD + MCT group) as a positive control, the second group received 6 g/d of MCTs (MCT group) as the test nutrient, and the third group received 6 g/d of long-chain triglycerides (LCT group) as a negative control. Cognition (secondary outcome) was monitored 4 times: baseline, 1.5 and 3 mo after initiation of the intervention (intervention), and 1.5 mo after termination of the intervention (postintervention follow-up). Cognition scores were assessed by a linear mixed model (intention-to-treat analysis). RESULTS: MCT supplementation increased the Mini-Mental State Examination (MMSE) score by 3.5 points at the 3-mo intervention from baseline (P < 0.001) [intention-to-treat adjusted means: baseline 17.5 points (95% CI: 14.9, 20.2), 3-mo intervention 21.0 points (18.3, 23.7)], whereas LCT supplementation decreased the MMSE score by -0.7 points [baseline 17.0 points (95% CI: 14.4, 19.6), 3-mo intervention 16.3 points (13.6, 18.9)]. At the 3-mo intervention, the difference in MMSE score between the MCT (21.0 points) and LCT (16.3 points) groups became significant (P < 0.05). The increase in MMSE score in response to MCTs was 2.1-fold greater at 3 mo than at 1.5 mo and had returned to baseline value at the 4.5-mo postintervention follow-up visit. CONCLUSION: Supplementation with 6 g MCTs/d may improve the cognition of frail elderly individuals. This trial was registered at umin.ac.jp as UMIN000023302.

Medium-chain triglycerides (8:0 and 10:0) are promising nutrients for sarcopenia: a randomized controlled trial.

BACKGROUND: The combined supplementation of medium-chain triglycerides (MCTs), l-leucine-rich amino acids, and cholecalciferol was previously shown to increase muscle strength and function in frail elderly individuals. OBJECTIVE: We examined whether treatment with MCTs alone is sufficient to increase muscle strength and function and activities of daily living (ADL) in such individuals. METHODS: We enrolled 64 elderly nursing home residents (85.5 ± 6.8 y) in a 3-mo randomized, controlled, single-blinded intervention trial. The participants were randomly assigned to 3 groups: the first group received supplemental l-leucine (1.2 g) and cholecalciferol (20 µg) enriched with 6 g/d of MCTs (LD + MCT group) as a positive control, the second group received 6 g/d of MCTs (MCT group) as a target, and the third group received 6 g/d of long-chain triglycerides (LCT group) as a negative control. Changes in muscle mass, strength, function, and ADL were monitored 4 times: at baseline, at 1.5 and 3 mo after initiation of the intervention (intervention), and 1.5 mo after termination of the intervention (washout). RESULTS: The 64 participants randomly assigned to the 3 groups were included in an intention-to-treat analysis. Forty-eight participants completed the study and were included in a per-protocol analysis. At 3 mo, participants in the MCT group had a 48.1% increase in 10-s leg open and close test performance [intention-to-treat adjusted means: MCT 2.28 n/10 s (1.37, 3.19) compared with LCT -0.59 n/10 s (-1.52, 0.35), P < 0.05], a 27.8% increase in a 30-s repetitive saliva swallowing test [MCT 0.5 n/30 s (0.1, 1.0) compared with LCT -0.5 n/30 s (-0.9, 0.0), P < 0.05], and a 7.5% increase in Functional Independence Measure score, a questionnaire for assessing ADL [MCT 5.6 points (1.3, 9.9) compared with LCT -6.6 points (-11.3, -2.0), P < 0.05]. CONCLUSION: MCTs (6 g/d) could increase the muscle strength and function of frail elderly individuals and also improve their ADL. This trial was registered at the University Hospital Medical Information Network Clinical Trial Registry as UMIN000023302.

High Dietary Saturated Fat is Associated with a Low Risk of Intracerebral Hemorrhage and Ischemic Stroke in Japanese but not in Non-Japanese: A Review and Meta-Analysis of Prospective Cohort Studies.

AIM: The associations between dietary saturated fatty acids and the risks of stroke subtypes in cohort studies were examined by a meta-analysis of separate ethnic Japanese and non-Japanese cohorts, and causes of their difference were elucidated. METHOD: Log hazard ratio (HR) with 95% confidence interval (CI) of the highest versus the lowest saturated fat intake from cohort studies were weighed by an inverse variance method to combine HRs. RESULTS: Five studies of intracerebral hemorrhage and 11 studies/comparisons of ischemic stroke were selected. A meta-analysis of intracerebral hemorrhage excluding subarachnoid hemorrhage showed a strong inverse association in Japanese (n=3, HR=0.55, 95% CI 0.32-0.94) but not in non-Japanese (n=2, HR=0.98, 95% CI 0.62-1.53). A meta-analysis of ischemic stroke showed a mild inverse association in Japanese (n=4, HR=0.82, 95% CI 0.71-0.93) but not in non-Japanese (n=7, HR= 0.93, 95% CI 0.84-1.03). The effect size of saturated fat in reducing the risk of stroke in Japanese was stronger for intracerebral hemorrhage (45% reduction) than for ischemic stroke (18% reduction). CONCLUSIONS: In Japanese but not in non-Japanese, a diet high in saturated fat is associated with a low risk of intracerebral hemorrhage and ischemic stroke. This may be due to differences in the range of intake of saturated fat, genetic susceptibility, incidence of lacunar infarction, and/or confounding factors such as dietary proteins. An intervention study targeting Japanese will be required to verify the causality.

Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle ß2-adrenergic receptor but not by AMPK.

Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of ß2-adrenergic receptor (AR), the major ß-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in ß-AR-deficient (ß-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of ß2-AR in the unilateral hind limb of ß-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and ß2-AR in muscle and in a manner independent of muscle AMPK.

Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Benefit Cognition in Frail Elderly Adults: A Randomized Controlled Trial.

The combined supplementation of medium-chain triglycerides (MCTs), L-leucine-rich amino acids, and cholecalciferol (vitamin D3) increase muscle strength and function in frail elderly individuals. However, their effects on cognition are unknown. We enrolled 38 elderly nursing home residents (mean age±SD, 86.6±4.8 y) in a 3-mo randomized, controlled, parallel group trial. The participants were randomly allocated to 3 groups: the first group received a L-leucine (1.2 g)- and cholecalciferol (20 µg)-enriched supplement with 6 g of MCT (LD+MCT); the second group received the same supplement with 6 g of long-chain triglycerides (LD+LCT); and the third group did not receive any supplements (control). Cognition was assessed at baseline and after the 3-mo intervention. The difference in changes among the groups was assessed with ANCOVA, adjusting for age and the baseline value as covariates. After 3 mo, the Mini-Mental State Examination (MMSE) score in the LD+MCT group increased by 10.6% (from 16.6 to 18.4 points, p<0.05). After 3 mo, the Nishimura geriatric rating scale for mental status (NM scale) score in the LD+MCT group increased by 30.6% (from 24.6 to 32.2 points, p<0.001), whereas that in the LD+LCT and control groups decreased by 11.2% (from 31.2 to 27.7 points, p<0.05) and 26.1% (from 27.2 to 20.1 points, p<0.001), respectively. The combined supplementation of MCTs (6 g), L-leucine-rich amino acids, and cholecalciferol may improve cognitive function in frail elderly individuals.

Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Increase Muscle Strength and Function in Frail Elderly Adults in a Randomized Controlled Trial.

BACKGROUND: Sarcopenia, the loss of skeletal muscle mass, strength, and function, is common in elderly individuals but difficult to treat. OBJECTIVE: A combination of nutrients was investigated to treat sarcopenia in very frail elderly adults. METHODS: We enrolled 38 elderly nursing home residents (11 men and 27 women with a mean ± SD age of 86.6 ± 4.8 y) in a 3-mo randomized, controlled, single-blind, parallel group trial. The participants were randomly allocated to 3 groups. The first group received a daily l-leucine (1.2 g) and cholecalciferol (20 µg)-enriched supplement with 6 g medium-chain triglycerides (TGs) (MCTs) (LD + MCT); the second group received the same leucine and cholecalciferol-enriched supplement with 6 g long-chain TGs (LD + LCT); and the third group did not receive any supplements (control). The supplement and oils were taken at dinner, and changes in muscle mass, strength, and function were monitored. RESULTS: The increase in body weight in the LD + MCT (1.1 ± 1.0 kg) and LD + LCT (0.8 ± 1.1 kg) groups was greater than that in the control group (-0.5 ± 0.9 kg) (P < 0.05). After 3 mo, participants in the LD + MCT group had a 13.1% increase in right-hand grip strength (1.2 ± 1.0 kg, P < 0.01), a 12.5% increase in walking speed (0.078 ± 0.080 m/s, P < 0.05), a 68.2% increase in a 10-s leg open-and-close test performance (2.31 ± 1.68 n/10 s, P < 0.001), and a 28.2% increase in peak expiratory flow (53 ± 59 L/min, P < 0.01). No significant improvements in muscle mass, strength, or function were observed in the LD + LCT or control groups. CONCLUSION: The combined supplementation of MCTs (6 g), leucine-rich amino acids, and cholecalciferol at dinner may improve muscle strength and function in frail elderly individuals. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000017567.

Nonexercise Activity Thermogenesis is Significantly Lower in Type 2 Diabetic Patients With Mental Disorders Than in Those Without Mental Disorders: A Cross-sectional Study.

Physical activity improves health in patients with mental disorders. Nonexercise activity thermogenesis (NEAT) represents energy expenditure due to daily physical activities other than volitional exercise. We aimed to evaluate NEAT in type 2 diabetic patients with and without accompanying mental disorders.Between September 2010 and September 2014, we studied 150 patients with type 2 diabetes, 50 of whom also had a diagnosis of mental disorder, such as schizophrenia or mood disorder. We evaluated their NEAT in structured interviews using a validated questionnaire, and investigated differences in NEAT score and metabolic parameters between patients with and without mental disorders.The NEAT score was significantly lower in patients with mental disorders than in those without (56.3 ±â€Š9.9 vs 61.9 ±â€Š12.1; P = 0.005). Patients with mental disorders had significantly higher triglyceride (184.5 ±â€Š116.3 vs 146.4 ±â€Š78.4 mg/dL; P = 0.02) and insulin levels (18.7 ±â€Š20.1 vs 11.2 ±â€Š8.5 µU/mL; P = 0.006), and significantly lower B-type natriuretic peptide (12.1 ±â€Š13.3 vs 26.3 ±â€Š24.8 pg/mL; P < 0.001) and brachial-ankle pulse wave velocity levels (1501 ±â€Š371 vs 1699 ±â€Š367 cm/s; P = 0.003) than patients without mental disorders. In patients with schizophrenia, specifically, NEAT showed a negative correlation with hemoglobin A1c levels (ß = -0.493, P = 0.031), and a positive correlation with high-density lipoprotein cholesterol (ß = 0.519, P = 0.023) and B-type natriuretic peptide levels (ß = 0.583, P = 0.02).Our results suggest that NEAT may be beneficial for the management of obesity, insulin sensitivity, and lipid profiles in patients with mental disorders. Incorporating NEAT into interventions for type 2 diabetes in patients with mental disorders, especially schizophrenia, shows promise and warrants further investigation.

Metabolomic Analysis of the Skeletal Muscle of Mice Overexpressing PGC-1α.

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors whose expression increases in the skeletal muscle during exercise. We have previously made transgenic mice overexpressing PGC-1α in the skeletal muscle (PGC-1α-Tg mice). PGC-1α upregulates the expression of genes associated with red fibers, mitochondrial function, fatty acid oxidation, and branched chain amino acid (BCAA) degradation. However, global analyses of the actual metabolic products have not been investigated. In this study, we conducted metabolomic analysis of the skeletal muscle in PGC-1α-Tg mice by capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry. Principal component analysis and hierarchical cluster analysis showed clearly distinguishable changes in the metabolites between PGC-1α-Tg and wild-type control mice. Changes were observed in metabolite levels of various metabolic pathways such as the TCA cycle, pentose phosphate pathway, nucleotide synthesis, purine nucleotide cycle, and amino acid metabolism, including BCAA and ß-alanine. Namely, metabolic products of the TCA cycle increased in PGC-1α-Tg mice, with increased levels of citrate (2.3-fold), succinate (2.2-fold), fumarate (2.8-fold), and malate (2.3-fold) observed. Metabolic products associated with the pentose phosphate pathway and nucleotide biosynthesis also increased in PGC-1α-Tg mice. Meanwhile, BCAA levels decreased (Val, 0.7-fold; Leu, 0.8-fold; and Ile, 0.7-fold), and Glu (3.1-fold) and Asp (2.2-fold) levels increased. Levels of ß-alanine and related metabolites were markedly decreased in PGC-1α-Tg mice. Coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, our metabolomics data showing the activation of the purine nucleotide pathway, malate-aspartate shuttle, as well as creatine metabolism, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise. Thus, we demonstrated the roles of PGC-1α in the skeletal muscle at the metabolite level.

Daily Physical Activity Assessed by a Triaxial Accelerometer Is Beneficially Associated with Waist Circumference, Serum Triglycerides, and Insulin Resistance in Japanese Patients with Prediabetes or Untreated Early Type 2 Diabetes.

AIM: To investigate the association between daily physical activity and metabolic risk factors in Japanese adults with prediabetes or untreated early type 2 diabetes (T2D). METHODS: Daily physical activity level was measured using a triaxial accelerometer. We assessed correlations between physical activity level and waist circumference, blood pressure, fasting levels of plasma glucose, serum triglycerides, and insulin and homeostasis model assessment-insulin resistance (HOMA-IR). RESULTS: A total of 80 patients were studied. After adjustment for age and body mass index, in all subjects, physical activity level was negatively associated with waist circumference (ß = -0.124, P = 0.018) and fasting serum triglycerides (ß = -0.239, P = 0.035), insulin (ß = -0.224, P = 0.022). In men, physical activity level was negatively associated with systolic blood pressure (ß = -0.351, P = 0.044), fasting plasma glucose (ß = -0.369, P = 0.025) and insulin (ß = -0.362, P = 0.012), and HOMA-IR (ß = -0.371, P = 0.011). No significant associations were found between physical activity level and metabolic risk factors in women. CONCLUSION: Objectively measured daily physical activity is beneficially associated with waist circumference, serum triglycerides, and insulin resistance in individuals with prediabetes or untreated early T2D. (This trial is registered with UMIN000015774.).

The association between daily physical activity and plasma B-type natriuretic peptide in patients with glucose intolerance: a cross-sectional study.

OBJECTIVES: In spite of accumulating evidences suggesting an inverse association between insulin resistance and plasma B-type natriuretic peptide (BNP) levels, the effect of daily physical activity on plasma BNP in individuals with glucose intolerance remains unknown. We investigated the association of physical activity level (PAL) with plasma BNP in patients with impaired fasting glucose, impaired glucose tolerance and type 2 diabetes. DESIGN: Cross-sectional study. SETTING: Outpatients visiting the National Center for Global Health and Medicine Kohnodai Hospital. PARTICIPANTS: A total of 60 patients with glucose intolerance who did not take any hypoglycaemic agents, cholesterol-lowering agents and antihypertensive agents were recruited. Patients who were diagnosed as having heart failure and renal impairment, engaged in sports-like exercise and resistance training were excluded. PRIMARY OUTCOME MEASURES: PAL was objectively measured by a triaxial accelerometer. The association between PAL and plasma BNP levels was assessed by multiple regression analysis. RESULTS: PAL was positively correlated with plasma BNP levels (r=0.296, p=0.021). PAL was still significantly correlated with plasma BNP levels after adjustment for age (ß=0.290, p=0.014), and adjustment for age and body mass index (ß=0.282, p=0.018). Plasma BNP levels were inversely correlated with serum insulin levels (r=-0.350, p=0.006) and homeostasis model assessment-estimated insulin resistance (HOMA-IR; r=-0.363, p=0.004). Serum insulin levels (mean±SD, 8.1±6.4 µU/mL) and HOMA-IR (2.4±1.9) in the high-BNP group were significantly lower than those (11.2±7.4 µU/mL and 3.7±3.0, respectively) in the low-BNP group. CONCLUSIONS: Our findings propose the possibility that plasma BNP may be increased by daily physical activity and BNP is associated with insulin resistance.

The validity of the non-exercise activity thermogenesis questionnaire evaluated by objectively measured daily physical activity by the triaxial accelerometer.

BACKGROUND: Physical inactivity is a major cardiovascular risk factor. Recently, we showed that non-exercise activity thermogenesis (NEAT) assessed by the self-reported questionnaire is favorably associated with metabolic risks in patients with type 2 diabetes. The purpose of the present study was to examine the validity of the questionnaire by comparing with objectively measured daily physical activity (PA) by using the triaxial accelerometer. METHODS: Daily physical activity level (PAL) of 51 participants (24 men and 27 women) with type 2 diabetes was measured by the triaxial accelerometer. At the same time, we evaluated their NEAT score using our original questionnaire modified from a compendium of physical activities. RESULTS: The NEAT score was significantly and positively correlated with PAL measured by the triaxial accelerometer (r = 0.604, P < 0.001). PAL was also significantly and positively correlated with both the locomotive NEAT score and the non-locomotive NEAT score (r = 0.444, P = 0.001 and r = 0.526, P < 0.001, respectively). CONCLUSIONS: The NEAT score measured by the self-reported questionnaire was highly correlated with PAL measured by the triaxial accelerometer. Our original NEAT questionnaire may be useful for evaluation of daily PAL in clinical practices.

The effects of PGC-1α on control of microvascular P(O2) kinetics following onset of muscle contractions.

During contractions, regulation of microvascular oxygen partial pressure (Pmv(O2)), which drives blood-myocyte O2 flux, is a function of skeletal muscle fiber type and oxidative capacity and can be altered by exercise training. The kinetics of Pmv(O2) during contractions in predominantly fast-twitch muscles evinces a more rapid fall to far lower levels compared with slow-twitch counterparts. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) improves endurance performance, in part, due to mitochondrial biogenesis, a fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. We tested the hypothesis that improvement of exercise capacity by genetic overexpression of PGC-1α would be associated with an altered Pmv(O2) kinetics profile of the fast-twitch (white) gastrocnemius during contractions toward that seen in slow-twitch muscles (i.e., slowed response kinetics and elevated steady-state Pmv(O2)). Phosphorescence quenching techniques were used to measure Pmv(O2) at rest and during separate bouts of twitch (1 Hz) and tetanic (100 Hz) contractions in gastrocnemius muscles of mice with overexpression of PGC-1α and wild-type littermates (WT) mice under isoflurane anesthesia. Muscles of PGC-1α mice exhibited less fatigue than WT (P < 0.01). However, except for the Pmv(O2) response immediately following onset of contractions, WT and PGC-1α mice demonstrated similar Pmv(O2) kinetics. Specifically, the time delay of the Pmv(O2) response was shortened in PGC-1α mice compared with WT (1 Hz: WT, 6.6 ± 2.4 s; PGC-1α, 2.9 ± 0.8 s; 100 Hz: WT, 3.3 ± 1.1 s, PGC-1α, 0.9 ± 0.3 s, both P < 0.05). The ratio of muscle force to Pmv(O2) was higher for the duration of tetanic contractions in PGC-1α mice. Slower dynamics and maintenance of higher Pmv(O2) following muscle contractions is not obligatory for improved fatigue resistance in fast-twitch muscle of PGC-1α mice. Moreover, overexpression of PGC-1α may accelerate O2 utilization kinetics to a greater extent than O2 delivery kinetics.

PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

Marked phenotypic differences of endurance performance and exercise-induced oxygen consumption between AMPK and LKB1 deficiency in mouse skeletal muscle: changes occurring in the diaphragm.

LKB1 phosphorylates members of the AMP-activated protein kinase (AMPK) family. LKB1 and AMPK in the skeletal muscle are believed to regulate not only fuel oxidation during exercise but also exercise capacity. LKB1 was also required to prevent diaphragm fatigue, which was shown to affect exercise performance. Using mice expressing dominant negative (DN) mutants of LKB1 and AMPK, specifically in the skeletal muscle but not in the heart, we investigated the roles of LKB1 and AMPK activity in exercise performance and the effects of these kinases on the characteristics of respiratory and locomotive muscles. In the diaphragm and gastrocnemius, both AMPK-DN and LKB1-DN mice showed complete loss of AMPKα2 activity, and LKB1-DN mice showed a reduction in LKB1 activity. Exercise capacity was significantly reduced in LKB1-DN mice, with a marked reduction in oxygen consumption and carbon dioxide production during exercise. The diaphragm from LKB1-DN mice showed an increase in myosin heavy chain IIB and glycolytic enzyme expression. Normal respiratory chain function and CPT I activity were shown in the isolated mitochondria from LKB1-DN locomotive muscle, and the expression of genes related to fiber type, mitochondria function, glucose and lipid metabolism, and capillarization in locomotive muscle was not different between LKB1-DN and AMPK-DN mice. We concluded that LKB1 in the skeletal muscle contributes significantly to exercise capacity and oxygen uptake during exercise. LKB1 mediated the change of fiber-type distribution in the diaphragm independently of AMPK and might be responsible for the phenotypes we observed.

Correlations of non-exercise activity thermogenesis to metabolic parameters in Japanese patients with type 2 diabetes.

BACKGROUND: Non-exercise activity thermogenesis (NEAT) is the energy expenditure due to physical activities besides active sports-like exercise and resistance training in daily life. METHODS: We studied 45 subjects (22 women and 23 men) with type 2 diabetes who did not take any hypoglycemic, anti-hypertensive, or cholesterol-lowering agents and asked them about physical activity concerned with NEAT using an original questionnaire modified from a compendium of physical activities. We studied the association of the NEAT score to body weight, waist circumference, blood pressure, glucose and lipid metabolism, and arterial stiffness. RESULTS: The NEAT score was negatively correlated with serum insulin levels (r = -0.42, P < 0.05) in all subjects. The NEAT score was also negatively correlated with waist circumference (r = -0.509, P < 0.05) and positively correlated with high-density lipoprotein-cholesterol levels (r = 0.494, P < 0.05) in women, and negatively associated with serum insulin levels (r = -0.732, p < 0.005), systolic (r = -0.482, P < 0.05) and diastolic blood pressure (r = -0.538, P < 0.05) in patients with abdominal obesity. Furthermore, the NEAT score was negatively associated with pulse wave velocity (r = -0.719, P < 0.005) in smokers. CONCLUSION: The study demonstrated that NEAT is associated with amelioration in insulin sensitivity, waist circumference, high-density lipoprotein-cholesterol, blood pressure and the marker for atherosclerosis in patients with type 2 diabetes.

Effects of intermittent physical activity on fat utilization over a whole day.

PURPOSE: We examined whether continuous and intermittent physical activity (PA) differentially influence fat utilization. METHODS: This was a randomized crossover study. Nine healthy young male participants performed two 39-h (two nights, three days) PA sessions (continuous and intermittent exercise) in a respiratory chamber to measure energy expenditure (EE) and substrate oxidation. Participants used a stationary cycling ergometer continuously for 40 min and then 45 min in the continuous PA trial and for 5 min every 30 min 17 times in the intermittent PA trial. They consumed high-carbohydrate meals corresponding to predicted daily total EE for 3 d before entering the respiratory chamber and four high-fat meals corresponding to predicted total EE in the chamber. RESULTS: Twenty-three-hour RER adjusted for sleeping RER on the preceding day was significantly lower in the intermittent PA trial than that in the continuous PA trial (P = 0.021). Twenty-three-hour RER adjusted for sleeping RER on the preceding day was correlated with accumulated consecutive minutes of METs ≤ 1.5 (3 min or more, r = 0.477; 5 min or more, r = 0.510; 10 min or more, r = 0.605). CONCLUSIONS: The intermittent PA trial induced greater fat utilization than the continuous PA trial. The present study, therefore, suggests that intermittent PA has a beneficial effect on 24-h fat oxidation after consumption of a high-fat meal, which may help prevent weight gain over time.