Biomedical subjects

Douglas Paddon-Jones

Publications and source records attributed to Douglas Paddon-Jones.

14 recordsLinked to original sources

PubMed2006

Atrophy and impaired muscle protein synthesis during prolonged inactivity and stress.

CONTEXT: We recently demonstrated that 28-d bed rest in healthy volunteers results in a moderate loss of lean leg mass and strength. OBJECTIVE: The objective of this study was to quantify changes in muscle protein kinetics, body composition, and strength during a clinical bed rest model reflecting both physical inactivity and the hormonal stress response to injury or illness. DESIGN: Muscle protein kinetics were calculated during a primed, continuous infusion (0.08 micromol/kg.min) of 13C6-phenylalanine on d 1 and 28 of bed rest. SETTING: The setting for this study was the General Clinical Research Center at the University of Texas Medical Branch. PARTICIPANTS: Participants were healthy male volunteers (n = 6, 28 +/- 2 yr, 84 +/- 4 kg, 178 +/- 3 cm). INTERVENTION: During bed rest, hydrocortisone sodium succinate was administered iv (d 1 and 28) and orally (d 2-27) to reproduce plasma cortisol concentrations consistent with trauma or illness (approximately 22 microg/dl). MAIN OUTCOME MEASURES: We hypothesized that inactivity and hypercortisolemia would reduce lean muscle mass, leg extension strength, and muscle protein synthesis. RESULTS: Volunteers experienced a 28.4 +/- 4.4% loss of leg extension strength (P = 0.012) and a 3-fold greater loss of lean leg mass (1.4 +/- 0.1 kg) (P = 0.004) compared with our previous bed rest-only model. Net protein catabolism was primarily due to a reduction in muscle protein synthesis [fractional synthesis rate, 0.081 +/- 0.004 (d 1) vs. 0.054 +/- 0.007%/h (d 28); P = 0.023]. There was no change in muscle protein breakdown. CONCLUSION: Prolonged inactivity and hypercortisolemia represents a persistent catabolic stimulus that exacerbates strength and lean muscle loss via a chronic reduction in muscle protein synthesis.

Adult↗

PubMed2006

Androgen therapy induces muscle protein anabolism in older women.

CONTEXT: Normal healthy men and women undergo a gradual loss of skeletal muscle mass and strength with advancing age. While androgens are protein anabolic in older men, the metabolic effects in older women are poorly understood. OBJECTIVE AND DESIGN: The objective of this study was to determine whether oral administration of a synthetic derivative of testosterone [oxandrolone, Oxandrin (OX)] (7.5 mg orally twice daily for 14 d) to five older women (age, 65 +/- 2 yr) would enhance skeletal muscle anabolic biomarkers including mixed muscle fractional synthetic rate (FSR), net phenylalanine balance, androgen receptor, and IGF-I protein expression at d 0, 5, and 14 of treatment. As a positive control, seven older men were examined after 14 d of OX (10 mg orally twice daily). SETTING: The study was performed at the General Clinical Research Center. RESULTS: Fourteen days of OX significantly increased skeletal muscle FSR in older women (d 0, 0.073 +/- 0.006 vs. d 5, 0.092 +/- 0.006 vs. d 14, 0.115 +/- 0.007%/h) (P < 0.05, d 0 vs. d 14). Conversely, OX stimulated FSR in older men after only 5 d (d 0, 0.061 +/- 0.003 vs. d 5, 0.101 +/- 0.01 vs. d 14, 0.084 +/- 0.01%/h) (P < 0.05, d 0 vs. d 5). Androgen receptor expression was significantly increased in older men by d 14, but had not increased in older women. No change was noted in IGF-I expression in either group. We conclude that the skeletal muscle of older women and men responds to androgen administration, although the time course of anabolism appears to be gender specific.

Aged↗

PubMed2006

Interplay of stress and physical inactivity on muscle loss: Nutritional countermeasures.

Inactivity-mediated protein catabolism occurs in many circumstances ranging from catastrophic events such as severe illness or injury, to unique environments such as spaceflight/microgravity, to more insidious causes such as physical frailty and the progression of aging. Nevertheless, regardless of the etiology, the consequences of inactivity are readily observable and debilitating. Mechanistically, the loss of lean body mass during inactivity is the result of a chronic imbalance between muscle protein synthesis and breakdown. When inactivity is accompanied by the stress of trauma or disease, the rate of muscle protein catabolism can increase several fold. Bed rest studies in healthy volunteers provide a unique opportunity to examine the mechanisms contributing to muscle loss and evaluate strategies for intervention that may slow muscle catabolism and promote anabolism. The prerequisite for muscle protein synthesis and the most readily adaptable stimulus is dietary-derived amino acids. This review focuses on the role of amino acid supplementation in the maintenance of skeletal muscle mass during age-related and clinically mandated inactivity.

Adult↗

PubMed2006

Bed rest and myopathies.

PURPOSE OF REVIEW: The loss of skeletal muscle with injury or critical illness can be dramatic. This review emphasizes the importance of skeletal muscle as a metabolic reserve. Changes in protein metabolism with bed rest alone and during physiological stress are discussed. Nutritional and hormonal interventions that ameliorate the loss of skeletal muscle are highlighted. RECENT FINDINGS: The loss of skeletal muscle that occurs with inactivity alone can be prevented by nutritional supplementation with an essential amino acid formula. Bed rest with accompanying hypercortisolemia produces a threefold greater loss of skeletal muscle than bed rest alone. Essential amino acids stimulate muscle anabolism during acute hypercortisolemia; however, their effects during chronic hypercortisolemia must be explored. SUMMARY: Skeletal muscle loss with trauma or critical illness is due in great part to the interaction of bed rest (muscular inactivity) and stress (hypercortisolemia). Younger individuals respond to nutritional and pharmacological interventions during bed rest alone. Given a lower relative lean mass in the elderly and the importance of skeletal muscle as a metabolic reserve during stress, it is understandable that clinical outcomes are worse in older patients. Countermeasures to the loss of skeletal muscle, especially in the stressed patient, must be developed.

Bed Rest↗

PubMed2005

Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein.

To counteract the debilitating progression of sarcopenia, a protein supplement should provide an energetically efficient anabolic stimulus. We quantified net muscle protein synthesis in healthy elderly individuals (65-79 yrs) following ingestion of an isocaloric intact whey protein supplement (WY; n=8) or an essential amino acid supplement (EAA; n=7). Femoral arterio-venous blood samples and vastus lateralis muscle biopsy samples were obtained during a primed, constant infusion of L-[ring-2H5]phenylalanine. Net phenylalanine uptake and mixed muscle fractional synthetic rate (FSR) were calculated during the post-absorptive period and for 3.5 h following ingestion of 15 g EAA or 15 g whey. After accounting for the residual increase in the intracellular phenylalanine pool, net post-prandial phenylalanine uptake was 53.4+/-9.7 mg phe leg-1 (EAA) and 21.7+/-4.6 mg phe leg-1 (WY), (P<0.05). Postabsorptive FSR values were 0.056+/-0.004% h-1 (EAA) and 0.049+/-0.006% h-1 (WY), (P>0.05). Both supplements stimulated FSR (P<0.05), but the increase was greatest in the EAA group with values of 0.088+/-0.011% h-1 (EAA) and 0.066+/-0.004% h-1 (WY), (P<0.05). While both EAA and WY supplements stimulated muscle protein synthesis, EAAs may provide a more energetically efficient nutritional supplement for elderly individuals.

Administration, Oral↗

PubMed2005

Amino acid supplementation for reversing bed rest and steroid myopathies.

Muscular inactivity is inherent in many circumstances, including convalescence from serious illness or injury, spaceflight, and the progression of aging. Inactivity in a healthy individual leads to a decrease in whole-body protein turnover composed primarily of a decrease in muscle protein synthesis. The decrease in muscle protein synthesis leads to a substantial loss of lean body mass. We have demonstrated that this loss of lean mass is greater when inactivity is accompanied by stress, specifically hypercortisolemia. During convalescence from trauma or injury, the anabolic stimulus provided by nutrient ingestion represents a primary means of ameliorating the loss of muscle protein. We have previously demonstrated that ingestion of essential amino acids (EAAs), formulated to mimic the proportion of EAAs in muscle, provides a potent anabolic stimulus for muscle protein. Recently, we demonstrated that EAA supplementation throughout 28 d of bed rest stimulated net muscle protein synthesis. The repeated stimulation translated to maintenance of lean body mass and an amelioration of functional decrement compared to a placebo treatment. We have also demonstrated that this EAA supplement stimulates net protein synthesis during acute hypercortisolemia and are currently testing the effects during prolonged inactivity. Although EAAs promote muscle anabolism during hypercortisolemia, it is unlikely that a nutritional intervention alone would be effective in maintaining lean body mass during severe stress. It may be necessary to concomitantly reduce the catabolic influence of cortisol or provide another anabolic stimulus.

Amino Acids↗

PubMed2004

The catabolic effects of prolonged inactivity and acute hypercortisolemia are offset by dietary supplementation.

We compared the anabolic stimulus provided by an essential amino acid and carbohydrate (AA/CHO) supplement to a mixed clinical meal during bed rest (BR) and episodic hypercortisolemia ( approximately 24 microg.dl(-1)). In the experimental (EXP; n = 7) and control (CON; n = 6) groups, femoral arteriovenous blood samples and vastus lateralis biopsy samples were obtained during a primed constant infusion of l-[ring-(2)H(5)]phenylalanine and a 14-h infusion of hydrocortisone sodium succinate (60 microg.kg.h(-1)) before (pre-BR) and after (post-BR) 28 d of BR. Muscle protein kinetics were calculated during the postabsorptive state, for 2.5 h after ingestion of a meal and for 2.5 h after ingestion of an AA/CHO supplement (EXP) or placebo (CON). Postabsorptive net phenylalanine balance values were as follows: EXP, -35.14 +/- 2.93, and CON, -32.60 +/- 6.65 (pre-BR); and EXP, -32.91 +/- 5.67, and CON, -30.43 +/- 6.28 nmol phe.ml(-1).100 ml leg volume(-1) (post-BR). After AA/CHO supplementation, net phenylalanine balance improved to 33.51 +/- 8.06 (pre-BR) and 24.15 +/- 11.4 nmol phe.ml(-1).100 ml leg volume(-1) (post-BR), but remained negative after the meal. Cumulative 5.5-h mixed muscle fractional synthetic rate was greater in the EXP group pre-BR (EXP, 0.108 +/- 0.01, and CON, 0.073 +/- 0.04%.h(-1)) and post-BR (EXP, 0.111 +/- 0.015, and CON, 0.05 +/- 0.002%.h(-1)). Unlike a typical clinical meal, AA/CHO supplementation stimulated net muscle protein synthesis despite acute hypercortisolemia and prolonged inactivity.

Adult↗

PubMed2004

Exogenous amino acids stimulate human muscle anabolism without interfering with the response to mixed meal ingestion.

We sought to determine whether ingestion of a between-meal supplement containing 30 g of carbohydrate and 15 g of essential amino acids (CAA) altered the metabolic response to a nutritionally mixed meal in healthy, recreationally active male volunteers. A control group (CON; n = 6, 38 +/- 8 yr, 86 +/- 10 kg, 179 +/- 3 cm) received a liquid mixed meal [protein, 23.4 +/- 1.0 g (essential amino acids, 14.7 +/- 0.7 g); carbohydrate, 126.6 +/- 4.0 g; fat, 30.3 +/- 2.8 g] every 5 h (0830, 1330, 1830). The experimental group (SUP; n = 7, 36 +/- 10 yr, 87 +/- 12 kg, 180 +/- 3 cm) consumed the same meals but, in addition, were given CAA supplements (1100, 1600, 2100). Net phenylalanine balance (NB) and fractional synthetic rate (FSR) were calculated during a 16-h primed constant infusion of L-[ring-2H5]phenylalanine. Ingestion of a combination of CAA supplements and meals resulted in a greater mixed muscle FSR than ingestion of the meals alone (SUP, 0.099 +/- 0.008; CON, 0.076 +/- 0.005%/h; P < 0.05). Both groups experienced an improvement in NB after the morning (SUP, -2.2 +/- 3.3; CON, -1.5 +/- 3.5 nmol x min(-1) x 100 ml leg volume(-1)) and evening meals (SUP, -9.7 +/- 4.3; CON, -6.7 +/- 4.1 nmol x min(-1) x 100 ml leg volume(-1)). NB after CAA ingestion was significantly greater than after the meals, with values of 40.2 +/- 8.5 nmol x min(-1) x 100 ml leg volume(-1). These data indicate that CAA supplementation produces a greater anabolic effect than ingestion of intact protein but does not interfere with the normal metabolic response to a meal.

Adult↗

PubMed2004

Potential ergogenic effects of arginine and creatine supplementation.

The rationale for the use of nutritional supplements to enhance exercise capacity is based on the assumption that they will confer an ergogenic effect above and beyond that afforded by regular food ingestion alone. The proposed or advertised ergogenic effect of many supplements is based on a presumptive metabolic pathway and may not necessarily translate to quantifiable changes in a variable as broadly defined as exercise performance. L-arginine is a conditionally essential amino acid that has received considerable attention due to potential effects on growth hormone secretion and nitric oxide production. In some clinical circumstances (e.g., burn injury, sepsis) in which the demand for arginine cannot be fully met by de novo synthesis and normal dietary intake, exogenous arginine has been shown to facilitate the maintenance of lean body mass and functional capacity. However, the evidence that supplemental arginine may also confer an ergogenic effect in normal healthy individuals is less compelling. In contrast to arginine, numerous studies have reported that supplementation with the arginine metabolite creatine facilitates an increase in anaerobic work capacity and muscle mass when accompanied by resistance training programs in both normal and patient populations. Whereas improvement in the rate of phosphocreatine resynthesis is largely responsible for improvements in acute work capacity, the direct effect of creatine supplementation on skeletal muscle protein synthesis is less clear. The purpose of this review is to summarize the role of arginine and its metabolite creatine in the context of a nutrition supplement for use in conjunction with an exercise stimulus in both healthy and patient populations.

Arginine↗

PubMed2004

Essential amino acid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest.

We determined whether essential amino acid and carbohydrate supplementation could offset the catabolic response to prolonged inactivity. Major outcome measures included mixed muscle fractional synthetic rate (FSR), phenylalanine net balance, lean leg mass, and leg extension strength. On d 1 and 28, vastus lateralis muscle biopsies and femoral arterio-venous blood samples were obtained during a primed constant infusion of l-[ring-(2)H(5)]phenylalanine. Net balance and FSR were calculated over 16 h, during which the control group (CON) received a nutritionally mixed meal every 5 h (0830, 1330, and 1830 h). The experimental group (EXP) also consumed 16.5 g essential amino acids and 30 g carbohydrate (1100, 1600, and 2100 h). The dietary regimen was maintained during bedrest. FSR was higher in the EXP group on d 1 (EXP, 0.099 +/- 0.008%/h; CON: 0.075 +/- 0.005%/h) and d 28 (EXP, 0.093 +/- 0.006%/h; CON, 0.055 +/- 0.007%/h). Lean leg mass was maintained throughout bedrest in the EXP group (+0.2 +/- 0.3 kg), but fell in the CON group (-0.4 +/- 0.1 kg). Strength loss was more pronounced in the CON group (EXP, -8.8 +/- 1.4 kg; CON, -17.8 +/- 4.4 kg). Essential amino acid and carbohydrate supplementation may represent a viable intervention for individuals at risk of sarcopenia due to immobility or prolonged bedrest.

Adult↗

PubMed2003

Amino acid ingestion improves muscle protein synthesis in the young and elderly.

We recently demonstrated that muscle protein synthesis was stimulated to a similar extent in young and elderly subjects during a 3-h amino acid infusion. We sought to determine if a more practical bolus oral ingestion would also produce a similar response in young (34 +/- 4 yr) and elderly (67 +/- 2 yr) individuals. Arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 micromol/kg) constant infusion (0.05 micromol.kg(-1).min(-1)) of L-[ring-2H5]phenylalanine. Muscle protein kinetics and mixed muscle fractional synthetic rate (FSR) were calculated before and after the bolus ingestion of 15 g of essential amino acids (EAA) in young (n = 6) and elderly (n = 7) subjects. After EAA ingestion, the rate of increase in femoral artery phenylalanine concentration was slower in elderly subjects but remained elevated for a longer period. EAA ingestion increased FSR in both age groups by approximately 0.04%/h (P < 0.05). However, muscle intracellular (IC) phenylalanine concentration remained significantly higher in elderly subjects at the completion of the study (young: 115.6 +/- 5.4 nmol/ml; elderly: 150.2 +/- 19.4 nmol/ml). Correction for the free phenylalanine retained in the muscle IC pool resulted in similar net phenylalanine uptake values in the young and elderly. EAA ingestion increased plasma insulin levels in young (6.1 +/- 1.2 to 21.3 +/- 3.1 microIU/ml) but not in elderly subjects (3.0 +/- 0.6 to 4.3 +/- 0.4 microIU/ml). Despite differences in the time course of plasma phenylalanine kinetics and a greater residual IC phenylalanine concentration, amino acid supplementation acutely stimulated muscle protein synthesis in both young and elderly individuals.

Administration, Oral↗

PubMed2003

Hypercortisolemia alters muscle protein anabolism following ingestion of essential amino acids.

Debilitating injury is accompanied by hypercortisolemia, muscle wasting, and disruption of the normal anabolic response to food. We sought to determine whether acute hypercortisolemia alters muscle protein metabolism following ingestion of a potent anabolic stimulus: essential amino acids (EAA). A 27-h infusion (80 microg. kg(-1). h(-1)) of hydrocortisone sodium succinate mimicked cortisol (C) levels accompanying severe injury (>30 microg/dl), (C + AA; n = 6). The control group (AA) received intravenous saline (n = 6). Femoral arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 micromol/kg) constant infusion (0.05 micromol. kg(-1). min(-1)) of l-[ring-(2)H(5)]phenylalanine before and after ingestion of 15 g of EAA. Hypercortisolemia [36.5 +/- 2.1 (C + AA) vs. 9.0 +/- 1.0 microg/dl (AA)] increased postabsorptive arterial, venous, and muscle intracellular phenylalanine concentrations. Hypercortisolemia also increased postabsorptive and post-EAA insulin concentrations. Net protein balance was blunted (40% lower) following EAA ingestion but remained positive for a greater period of time (60 vs. 180 min) in the C + AA group. Thus, although differences in protein metabolism were evident, EAA ingestion improved muscle protein anabolism during acute hypercortisolemia and may help minimize muscle loss following debilitating injury.

Administration, Oral↗

PubMed2003

Differential anabolic effects of testosterone and amino acid feeding in older men.

The interaction between testosterone and exogenous amino acids was studied in older men before and after 6 months of testosterone administration. Twelve healthy older male subjects were randomly assigned in double-blind fashion to receive either testosterone enanthate [T; n = 7; 68 +/- 3 (+/-SE) yr] or placebo (n = 5; 67 +/- 3 yr) for 6 months. Muscle protein kinetics were determined using stable isotope methodology, arterial-venous difference across leg muscle, and muscle biopsies. In addition, ubiquitin-proteasome activity was measured in muscle biopsies as an indicator of muscle protein breakdown. T improved fasting net protein balance, although it remained significantly negative. The improvement in net balance was due to a decrease in muscle protein breakdown, as protein synthesis was unchanged. Ubiquitin-proteasome activity was also decreased with T. Exogenous amino acids increased protein synthesis in both placebo and T groups, but to a lesser degree after 6 months of T treatment. These results indicate that prolonged T administration increases net protein balance in the fasted state, but no additive effect is demonstrated when combined with amino acid feedings. Taken together, however, these diverse stimulatory effects can increase lean body mass and muscle strength over time.

Aged↗

PubMed2002

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.

Adult↗