2,000 Steps/Day Does Not Fully Protect Skeletal Muscle Health in Older Adults During Bed Rest.

Physical activity in an inpatient setting is often limited to brief periods of walking. For healthy adults, public health agencies recommend a minimum of 150 min/week of moderate-intensity exercise. The authors sought to determine if meeting this activity threshold, in the absence of incidental activities of daily living, could protect skeletal muscle health during bed rest. Healthy older adults (68 ± 2 years) were randomized to 7-day bed rest with (STEP, n = 7) or without (CON, n = 10) a 2,000 steps/day intervention. Performing 2018 ± 4 steps/day did not prevent the loss of lean leg mass and had no beneficial effect on aerobic capacity, strength, or muscle fiber volume. However, the insulin response to an oral glucose challenge was preserved. Performing a block of 2,000 steps/day, in the absence of incidental activities of daily living, was insufficient to fully counter the catabolic effects of bed rest in healthy older adults.

Adopting a Mediterranean-Style Eating Pattern with Different Amounts of Lean Unprocessed Red Meat Does Not Influence Short-Term Subjective Personal Well-Being in Adults with Overweight or Obesity.

Background: Reducing red meat intake is commonly recommended. Limited observational studies suggest that healthy eating patterns with red meat are associated with improved quality of life. Objective: The secondary objectives of this randomized crossover controlled-feeding trial were to assess the effects of following a Mediterranean-style eating pattern (Med-Pattern) with different amounts of red meat on indexes of personal well-being (i.e., perceived quality of life, mood, and sleep) in overweight or obese adults. We hypothesized that following a Med-Pattern would improve these outcomes, independent of red meat intake amount. Methods: Forty-one participants [aged 46 ± 2 y; body mass index (kg/m2): 30.5 ± 0.6; n = 28 women, n = 13 men) were provided Med-Pattern foods for two 5-wk periods separated by 4 wk of self-selected eating. The Med-Red Pattern contained ∼500 g/wk (typical US intake), and the Med-Control Pattern contained ∼200 g/wk (commonly recommended intake in heart-healthy eating patterns) of lean, unprocessed beef or pork compensated with mainly poultry and dairy. Baseline and postintervention outcomes measured were perceived quality of life via the MOS 36-Item Short-Form Health Survey, version 2 (SF-36v2), daily mood states via the Profile of Mood States (POMS), sleep perceptions via the Pittsburgh Sleep Quality Index, and sleep patterns via actigraphy. Data were analyzed via a doubly repeated-measures ANOVA adjusted for age, sex, and body mass at each time point. Results: Following a Med-Pattern did not change domains of physical health, mental health, total mood disturbances, sleep perceptions, and sleep patterns but improved subdomains of physical health role limitations (SF-36v2: 93.6-96.7%; P = 0.038), vitality (SF-36v2: 57.9-63.0%; P = 0.020), and fatigue (POMS: 2.9-2.5 arbitrary units; P = 0.039). There were no differences between the Med-Red and Med-Control Patterns (time × pattern, P-interaction > 0.05). Conclusion: Following a Med-Pattern, independent of lean, unprocessed red meat intake, may not be an effective short-term strategy to meaningfully improve indexes of personal well-being in adults who are overweight or obese. This trial was registered at clinicaltrials.gov as NCT02573129.

Dietary protein and muscle in older persons.

PURPOSE OF REVIEW: The purpose of this study is to highlight recent advances in nutrition and protein research that have the potential to improve health outcomes and status in ageing adults. RECENT FINDINGS: The beneficial effects of dietary protein on muscle health in older adults continue to be refined. Recent research has bolstered support for moderately increasing protein consumption beyond the current Recommended Dietary Allowance by adopting a meal-based approach in lieu of a less specific daily recommendation. Results from muscle protein anabolism, appetite regulation and satiety research support the contention that meeting a protein threshold (approximately 30 g/meal) represents a promising strategy for middle-aged and older adults concerned with maintaining muscle mass while controlling body fat. SUMMARY: Optimizing dietary protein intake to improve health requires a detailed consideration of topics including muscle protein anabolism, appetite control and satiety. Although each area of research continues to advance independently, recent collaborative and translational efforts have highlighted broad, translational consistencies related to the daily distribution and quantity of dietary protein.

Dietary protein distribution positively influences 24-h muscle protein synthesis in healthy adults.

The RDA for protein describes the quantity that should be consumed daily to meet population needs and to prevent deficiency. Protein consumption in many countries exceeds the RDA; however, intake is often skewed toward the evening meal, whereas breakfast is typically carbohydrate rich and low in protein. We examined the effects of protein distribution on 24-h skeletal muscle protein synthesis in healthy adult men and women (n = 8; age: 36.9 ± 3.1 y; BMI: 25.7 ± 0.8 kg/m2). By using a 7-d crossover feeding design with a 30-d washout period, we measured changes in muscle protein synthesis in response to isoenergetic and isonitrogenous diets with protein at breakfast, lunch, and dinner distributed evenly (EVEN; 31.5 ± 1.3, 29.9 ± 1.6, and 32.7 ± 1.6 g protein, respectively) or skewed (SKEW; 10.7 ± 0.8, 16.0 ± 0.5, and 63.4 ± 3.7 g protein, respectively). Over 24-h periods on days 1 and 7, venous blood samples and vastus lateralis muscle biopsy samples were obtained during primed (2.0 µmol/kg) constant infusion [0.06 µmol/(kg⋅min)] of l-[ring-(13)C6]phenylalanine. The 24-h mixed muscle protein fractional synthesis rate was 25% higher in the EVEN (0.075 ± 0.006%/h) vs. the SKEW (0.056 ± 0.006%/h) protein distribution groups (P = 0.003). This pattern was maintained after 7 d of habituation to each diet (EVEN vs. SKEW: 0.077 ± 0.006 vs. 0.056 ± 0.006%/h; P = 0.001). The consumption of a moderate amount of protein at each meal stimulated 24-h muscle protein synthesis more effectively than skewing protein intake toward the evening meal.

Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults.

Skeletal muscle atrophy during bed rest is attributed, at least in part, to slower basal muscle protein synthesis (MPS). Essential amino acids (EAA) stimulate mammalian target of rapamycin (mTORC1) signaling, amino acid transporter expression, and MPS and are necessary for muscle mass maintenance, but there are no data on the effect of inactivity on this anabolic mechanism. We hypothesized that bed rest decreases muscle mass in older adults by blunting the EAA stimulation of MPS through reduced mTORC1 signaling and amino acid transporter expression in older adults. Six healthy older adults (67 ± 2 yr) participated in a 7-day bed rest study. We used stable isotope tracers, Western blotting, and real-time qPCR to determine the effect of bed rest on MPS, muscle mTORC1 signaling, and amino acid transporter expression and content in the postabsorptive state and after acute EAA ingestion. Bed rest decreased leg lean mass by ∼4% (P < 0.05) and increased postabsorptive mTOR protein (P < 0.05) levels while postabsorptive MPS was unchanged (P > 0.05). Before bed rest acute EAA ingestion increased MPS, mTOR (Ser(2448)), S6 kinase 1 (Thr(389), Thr(421)/Ser(424)), and ribosomal protein S6 (Ser(240/244)) phosphorylation, activating transcription factor 4, L-type amino acid transporter 1 and sodium-coupled amino acid transporter 2 protein content (P < 0.05). However, bed rest blunted the EAA-induced increase in MPS, mTORC1 signaling, and amino acid transporter protein content. We conclude that bed rest in older adults significantly attenuated the EAA-induced increase in MPS with a mechanism involving reduced mTORC1 signaling and amino acid transporter protein content. Together, our data suggest that a blunted EAA stimulation of MPS may contribute to muscle loss with inactivity in older persons.

The T allele of TCF7L2 rs7903146 is associated with decreased glucose tolerance after bed rest in healthy older adults.

Inpatient populations are at increased risk of hyperglycemia due to factors such as medications, physical inactivity and underlying illness, which increases morbidity and mortality. Unfortunately, clinicians have limited tools available to prospectively identify those at greatest risk. We evaluated the ability of 10 common genetic variants associated with development of type 2 diabetes to predict impaired glucose metabolism. Our research model was a simulated inpatient hospital stay (7 day bed rest protocol, standardized diet, and physical inactivity) in a cohort of healthy older adults (n = 31, 65 ± 8 years) with baseline fasting blood glucose < 100 mg/dL. Participants completed a standard 75 g oral glucose tolerance test (OGTT) at baseline and post-bed rest. Bed rest increased 2-h OGTT blood glucose and insulin independent of genetic variant. In multiple regression modeling, the transcription factor 7-like 2 (TCF7L2) rs7903146 T allele predicted increases in 2-h OGTT blood glucose (p = 0.039). We showed that the TCF7L2 rs7903146 T allele confers risk for loss of glucose tolerance in nondiabetic older adults following 7 days of bed rest.

Age-related anabolic resistance after endurance-type exercise in healthy humans.

Age-related skeletal muscle loss is thought to stem from suboptimal nutrition and resistance to anabolic stimuli. Impaired microcirculatory (nutritive) blood flow may contribute to anabolic resistance by reducing delivery of amino acids to skeletal muscle. In this study, we employed contrast-enhanced ultrasound, microdialysis sampling of skeletal muscle interstitium, and stable isotope methodology, to assess hemodynamic and metabolic responses of older individuals to endurance type (walking) exercise during controlled amino acid provision. We hypothesized that older individuals would exhibit reduced microcirculatory blood flow, interstitial amino acid concentrations, and amino acid transport when compared with younger controls. We report for the first time that aging induces anabolic resistance following endurance exercise, manifested as reduced (by ∼40%) efficiency of muscle protein synthesis. Despite lower (by ∼40-45%) microcirculatory flow in the older than in the younger participants, circulating and interstitial amino acid concentrations and phenylalanine transport into skeletal muscle were all equal or higher in older individuals than in the young, comprehensively refuting our hypothesis that amino acid availability limits postexercise anabolism in older individuals. Our data point to alternative mediators of age-related anabolic resistance and importantly suggest correction of these impairments may reduce requirements for, and increase the efficacy of, dietary protein in older individuals.

Leucine augments specific skeletal muscle mitochondrial respiratory pathways during recovery following 7 days of physical inactivity in older adults.

In older adults, leucine mitigated the loss of insulin sensitivity associated with muscular disuse. Leucine supplementation increased mitochondrial respiration and reduced a marker of oxidative stress following periods of disuse and rehabilitation.

The effect of acute sleep deprivation on skeletal muscle protein synthesis and the hormonal environment.

Chronic sleep loss is a potent catabolic stressor, increasing the risk of metabolic dysfunction and loss of muscle mass and function. To provide mechanistic insight into these clinical outcomes, we sought to determine if acute sleep deprivation blunts skeletal muscle protein synthesis and promotes a catabolic environment. Healthy young adults (N = 13; seven male, six female) were subjected to one night of total sleep deprivation (DEP) and normal sleep (CON) in a randomized cross-over design. Anabolic and catabolic hormonal profiles were assessed across the following day. Postprandial muscle protein fractional synthesis rate (FSR) was assessed between 13:00 and 15:00 and gene markers of muscle protein degradation were assessed at 13:00. Acute sleep deprivation reduced muscle protein synthesis by 18% (CON: 0.072 ± 0.015% vs. DEP: 0.059 ± 0.014%·h-1 , p = .040). In addition, sleep deprivation increased plasma cortisol by 21% (p = .030) and decreased plasma testosterone by 24% (p = .029). No difference was found in the markers of protein degradation. A single night of total sleep deprivation is sufficient to induce anabolic resistance and a procatabolic environment. These acute changes may represent mechanistic precursors driving the metabolic dysfunction and body composition changes associated with chronic sleep deprivation.

Protecting muscle mass and function in older adults during bed rest.

PURPOSE OF REVIEW: To highlight the losses in muscle mass, strength, power, and functional capacity incurred in older adults during bed rest-mediated inactivity and to provide practical recommendations for both the prevention and rehabilitation of these losses. RECENT FINDINGS: In addition to sarcopenic muscle loss, older adults lose lean tissue more rapidly than the young during prolonged periods of physical inactivity. Amino acid or protein supplementation has the potential to maintain muscle protein synthesis and may reduce inactivity-induced muscle loss, but should ideally be part of an integrated countermeasure regimen consisting of nutrition, exercise, and, when appropriate, pharmacologic interventions. SUMMARY: In accordance with recent mechanistic advances, we recommend an applied, broad-based two-phase approach to limit inactivity-mediated losses of muscle mass and function in older adults: (i) Lifestyle: consume a moderate amount (25-30 g) of high-quality protein with each meal and incorporate habitual exercise in close temporal proximity to protein-containing meals; (ii) Crises: react aggressively to combat the accelerated loss of muscle mass and function during acute catabolic crises and periods of reduced physical activity. As a base strategy, this should include nutritional support such as targeted protein or amino acid supplementation and integrated physical therapy.

Optimizing Adult Protein Intake During Catabolic Health Conditions.

The DRIs define a range of acceptable dietary intakes for each nutrient. The range is defined from the minimum intake to avoid risk of inadequacy (i.e., the RDA) up to an upper limit (UL) based on a detectable risk of adverse effects. For most nutrients, the minimum RDA is based on alleviating a clear deficiency condition, whereas higher intakes are often recommended to optimize specific health outcomes. Evidence is accumulating that similar logic should be applied to dietary recommendations for protein. Although the RDA for protein of 0.8 g/kg body weight is adequate to avoid obvious inadequacies, multiple studies provide evidence that many adults may benefit from protein quantity, quality, and distribution beyond guidelines currently defined by the RDA. Further, the dietary requirement for protein is a surrogate for the constituent amino acids and, in particular, the 9 considered to be indispensable. Leucine provides an important example of an essential amino acid where the RDA of 42 mg/kg body weight is significantly less than the 100-110 mg/kg required to optimize metabolic regulation and skeletal muscle protein synthesis. This review will highlight the benefits of higher protein diets to optimize health during aging, inactivity, bed rest, or metabolic dysfunction such as type 2 diabetes.

Countering disuse atrophy in older adults with low-volume leucine supplementation.

Older adults are at increased risk of being bedridden and experiencing negative health outcomes including the loss of muscle tissue and functional capacity. We hypothesized that supplementing daily meals with a small quantity (3-4 g/meal) of leucine would partially preserve lean leg mass and function of older adults during bed rest. During a 7-day bed rest protocol, followed by 5 days of inpatient rehabilitation, healthy older men and women (67.8 ± 1.1 yr, 14 men; 6 women) were randomized to receive isoenergetic meals supplemented with leucine (LEU, 0.06 g/kg/meal; n = 10) or an alanine control (CON, 0.06 g/kg/meal; n = 10). Outcomes were assessed at baseline, following bed rest, and after rehabilitation. Body composition was measured by dual-energy X-ray absorptiometry. Functional capacity was assessed by knee extensor isokinetic and isometric dynamometry, peak aerobic capacity, and the short physical performance battery. Muscle fiber type, cross-sectional area, signaling protein expression levels, and single fiber characteristics were determined from biopsies of the vastus lateralis. Leucine supplementation reduced the loss of leg lean mass during bed rest (LEU vs. CON: -423 vs. -1035 ± 143 g; P = 0.008) but had limited impact on strength or endurance-based functional outcomes. Similarly, leucine had no effect on markers of anabolic signaling and protein degradation during bed rest or rehabilitation. In conclusion, providing older adults with supplemental leucine has minimal impact on total energy or protein consumption and has the potential to partially counter some, but not all, of the negative effects of inactivity on muscle health.NEW & NOTEWORTHY Skeletal muscle morphology and function in older adults was significantly compromised by 7 days of disuse. Leucine supplementation partially countered the loss of lean leg mass but did not preserve muscle function or positively impact changes at the muscle fiber level associated with bed rest or rehabilitation. Of note, our data support a relationship between myonuclear content and adaptations to muscle atrophy at the whole limb and single fiber level.

Dietary protein recommendations and the prevention of sarcopenia.

PURPOSE OF REVIEW: To draw attention to recent work on the role of protein and the amount of protein needed with each meal to preserve skeletal muscle mass in ageing. RECENT FINDINGS: Ageing does not inevitably reduce the anabolic response to a high-quality protein meal. Ingestion of approximately 25-30 g of protein per meal maximally stimulates muscle protein synthesis in both young and older individuals. However, muscle protein synthesis is blunted in elderly when protein and carbohydrate are coingested or when the quantity of protein is less than approximately 20 g per meal. Supplementing regular mixed-nutrient meals with leucine may also enhance the muscle protein synthetic response in elders. SUMMARY: On the basis of recent work, we propose a novel and specific dietary approach to prevent or slow down muscle loss with ageing. Rather than recommending a large, global increase in the recommended dietary allowance (RDA) for protein for all elderly individuals, clinicians should stress the importance of ingesting a sufficient amount of protein with each meal. To maximize muscle protein synthesis while being cognizant of total energy intake, we propose a dietary plan that includes 25-30 g of high quality protein per meal.

Improving Dietary Protein Quality Reduces the Negative Effects of Physical Inactivity on Body Composition and Muscle Function.

BACKGROUND: Brief periods of physical inactivity can compromise muscle health. Increasing dietary protein intake is potentially beneficial but complicated by difficulties reconciling anabolic potential with a realistic food volume and energy intake. We sought to determine whether increasing dietary protein quality could reduce the negative effects of physical inactivity. METHODS: Twenty healthy, older men and women completed 7 days of bed rest followed by 5 days of rehabilitation. Volunteers consumed a mixed macronutrient diet (MIXED: N = 10; 68 ± 2 years; 1,722 ± 29 kcal/day; 0.97 ± 0.01 g protein/kg/day) or an isoenergetic, whey-augmented, higher protein quality diet (WHEY: N = 10; 69 ± 1 years; 1,706 ± 23 kcal/day; 0.90 ± 0.01 g protein/kg/day). Outcomes included body composition, blood glucose, insulin, and a battery of physical function tests. RESULTS: During bed rest, both groups experienced a 20% reduction in knee extension peak torque (p < .05). The WHEY diet partially protected leg lean mass (-1,035 vs. -680 ± 138 g, MIXED vs. WHEY; p = .08) and contributed to a greater loss of body fat (-90 vs. -233 ± 152 g, MIXED vs. WHEY; p < .05). Following rehabilitation, knee extension peak torque in the WHEY group fully recovered (-10.0 vs. 2.2 ± 4.1 Nm, MIXED vs. WHEY; p = .05). Blood glucose, insulin, aerobic capacity, and Short Physical Performance Battery (SPPB) changes were similar in both dietary conditions (p > .05). CONCLUSIONS: Improving protein quality without increasing total energy intake has the potential to partially counter some of the negative effects of bed rest in older adults.

Functional impact of 10 days of bed rest in healthy older adults.

BACKGROUND: Many older individuals decline functionally during hospitalization, and the deleterious consequences of bed rest may be one cause. This study reports on the effect of 10 days of bed rest on multiple functional parameters in healthy older adults. METHODS: Healthy older men and women (n = 11, 67 +/- 5 years old) remained on bed rest for 10 days continuously, and consumed a eucaloric diet providing the Recommended Dietary Allowance for protein. Measures of lower extremity strength and power, aerobic capacity and physical performance, as well as physical activity were performed before and after bed rest. RESULTS: All measures of lower extremity strength were significantly lower after bed rest including isotonic knee extensor strength (-13.2 +/- 4.1%, p =.004) and stair-climbing power (-14 +/- 4.1%, p =.01). Maximal aerobic capacity was 12% lower after bed rest (p =.04), whereas measures of physical performance (Short Physical Performance Battery, and a five-item physical performance test) were not significantly different. Voluntary physical activity decreased after bed rest, and the percentage of time spent inactive increased (7.6 +/- 1.8%, p =.004). There were no medical complications. CONCLUSIONS: In healthy older adults, 10 days of bed rest results in a substantial loss of lower extremity strength, power, and aerobic capacity, and a reduction in physical activity, but has no effect on physical performance. Identification of interventions to maintain muscle function during hospitalization or periods of bed rest in older adults should be a high priority.

A Mediterranean-style eating pattern with lean, unprocessed red meat has cardiometabolic benefits for adults who are overweight or obese in a randomized, crossover, controlled feeding trial.

Background: A Mediterranean-style eating pattern (Mediterranean Pattern) is often described as being low in red meat. Research shows that lean, unprocessed red meat can be incorporated into healthy eating patterns to improve cardiometabolic disease (CMD) risk factors. Objective: We assessed the effects of consuming different amounts of lean, unprocessed red meat in a Mediterranean Pattern on CMD risk factors. We hypothesized that consuming a Mediterranean Pattern would improve CMD risk factors and that red meat intake would not influence these improvements. Design: In an investigator-blinded, randomized, crossover, controlled feeding trial, 41 subjects [mean ± SD age: 46 ± 2 y; mean ± SD body mass index (kg/m2): 30.5 ± 0.6] were provided with a Mediterranean Pattern for two 5-wk interventions separated by 4 wk of self-selected eating. The Mediterranean Patterns contained ∼500 g [typical US intake (Med-Red)] and ∼200 g [commonly recommended intake in heart-healthy eating patterns (Med-Control)] of lean, unprocessed beef or pork per week. Red meat intake was compensated by poultry and other protein-rich foods. Baseline and postintervention outcomes included fasting blood pressure, serum lipids, lipoproteins, glucose, insulin, and ambulatory blood pressure. The presented results were adjusted for age, sex, and body mass at each time point (P < 0.05). Results: Total cholesterol decreased, but greater reductions occurred with Med-Red than with Med-Control (-0.4 ± 0.1 and -0.2 ±0.1 mmol/L, respectively, intervention × time = 0.045]. Low-density lipoprotein decreased with Med-Red but was unchanged with Med-Control [-0.3 ± 0.1 and -0.1 ± 0.1 mmol/L, respectively, intervention × time = 0.038], whereas high-density lipoprotein (HDL) concentrations decreased nondifferentially [-0.1 ± 0.0 mmol/L]. Triglycerides, total cholesterol:HDL, glucose, and insulin did not change with either Med-Red or Med-Control. All blood pressure parameters improved, except during sleep, independent of the red meat intake amount. Conclusions: Adults who are overweight or moderately obese may improve multiple cardiometabolic disease risk factors by adopting a Mediterranean-style eating pattern with or without reductions in red meat intake when red meats are lean and unprocessed. This trial was registered at clinicaltrials.gov as NCT02573129.

Aging does not impair the anabolic response to a protein-rich meal.

BACKGROUND: Sarcopenia is a debilitating condition afflicting the elderly that may be facilitated by insufficient or ineffectual intake of dietary protein. We previously showed that free-form essential amino acids acutely stimulate muscle protein synthesis in both the young and the elderly. However, the ability of an actual protein-rich food to stimulate anabolism in the young and the elderly has not been explored. OBJECTIVE: We aimed to characterize changes in plasma amino acid concentrations and to quantify muscle protein synthesis in healthy young (41 +/- 8 y old; n = 10) and elderly (70 +/- 5 y old; n = 10) persons after ingestion of a 113-g (4-oz) serving of lean beef. DESIGN: Venous blood samples and vastus lateralis muscle biopsy samples were obtained during a primed (2.0 mumol/kg) constant infusion (0.08 mumol.kg(-1).min(-1)) of l-[ring-(13)C(6)] phenylalanine. Plasma amino acid concentrations were measured and a mixed-muscle fractional synthesis rate (FSR) was calculated during the premeal period and for 5 h after beef ingestion. RESULTS: Mixed-muscle FSR increased by approximately 51% in both the elderly (mean +/- SE measurements: 0.072 +/- 0.004%/h and 0.108 +/- 0.006%/h before and after the meal, respectively) and the young (0.074 +/- 0.005%/h and 0.113 +/- 0.005%/h before and after the meal, respectively) after beef ingestion (P < 0.001). Plasma amino acid concentrations peaked at approximately 100 min after beef ingestion in both age groups but were substantially higher in the elderly (2185 +/- 134 nmol/mL compared with 1403 +/- 96 nmol/mL; P < 0.001). CONCLUSION: Despite differences in the concentration of amino acids in the plasma precursor pool, aging does not impair the ability to acutely synthesize muscle protein after ingestion of a common protein-rich food.

Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle.

Physiological hyperglycemia with hyperinsulinemia reduces fat oxidation in skeletal muscle. The mechanism responsible for this decrease in fat oxidation in human muscle is not known and may contribute to the development of insulin resistance. We hypothesized that the transfer of long-chain fatty acids (LCFAs) into the mitochondria via carnitine palmitoyltransferase-1 (CPT-1) is inhibited by increased malonyl coenzyme A (malonyl-CoA) (a known potent inhibitor of CPT-1) in human muscle during hyperglycemia with hyperinsulinemia. We studied six healthy subjects after an overnight fast and during an induced 5-hour period of hyperglycemia with hyperinsulinemia. Muscle fatty acid oxidation was calculated using stable isotope methodology combined with blood sampling from the femoral artery and vein of one leg. Muscle functional CPT-1 activity was assessed by concurrently infusing an LCFA tracer and a CPT-independent medium-chain fatty acid tracer. Muscle biopsies were obtained from the vastus lateralis after the periods of fasting and hyperglycemia with hyperinsulinemia. Hyperglycemia with hyperinsulinemia decreased LCFA oxidation, but had no effect on LCFA uptake or medium-chain fatty acid oxidation across the leg. Malonyl-CoA concentration significantly increased from 0.13 +/- 0.01 to 0.35 +/- 0.07 nmol/g during hyperglycemia with hyperinsulinemia. We conclude that hyperglycemia with hyperinsulinemia increases malonyl-CoA, inhibits functional CPT-1 activity, and shunts LCFA away from oxidation and toward storage in human muscle.