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1.
Aging Cell ; 20(2): e13303, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33464721

RESUMEN

Intramyocellular lipid (IMCL) utilization is impaired in older individuals, and IMCL accumulation is associated with insulin resistance. We hypothesized that increasing muscle total carnitine content in older men would increase fat oxidation and IMCL utilization during exercise, and improve insulin sensitivity. Fourteen healthy older men (69 ± 1 year, BMI 26.5 ± 0.8 kg/m2 ) performed 1 h of cycling at 50% VO2 max and, on a separate occasion, underwent a 60 mU/m2 /min euglycaemic hyperinsulinaemic clamp before and after 25 weeks of daily ingestion of a 220 ml insulinogenic beverage (44.4 g carbohydrate, 13.8 g protein) containing 4.5 g placebo (n = 7) or L-carnitine L-tartrate (n = 7). During supplementation, participants performed twice-weekly cycling for 1 h at 50% VO2 max. Placebo ingestion had no effect on muscle carnitine content or total fat oxidation during exercise at 50% VO2 max. L-carnitine supplementation resulted in a 20% increase in muscle total carnitine content (20.1 ± 1.2 to 23.9 ± 1.7 mmol/kg/dm; p < 0.01) and a 20% increase in total fat oxidation (181.1 ± 15.0 to 220.4 ± 19.6 J/kg lbm/min; p < 0.01), predominantly due to increased IMCL utilization. These changes were associated with increased expression of genes involved in fat metabolism (ACAT1, DGKD & PLIN2; p < 0.05). There was no change in resting insulin-stimulated whole-body or skeletal muscle glucose disposal after supplementation. This is the first study to demonstrate that a carnitine-mediated increase in fat oxidation is achievable in older individuals. This warrants further investigation given reduced lipid turnover is associated with poor metabolic health in older adults.


Asunto(s)
Carnitina/metabolismo , Ejercicio Físico , Grasas/metabolismo , Músculo Esquelético/metabolismo , Anciano , Humanos , Masculino , Oxidación-Reducción
2.
Clin Nutr ; 36(3): 888-895, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27208923

RESUMEN

Maximizing anabolic responses to feeding and exercise is crucial for muscle maintenance and adaptation to exercise training. We hypothesized that enriching a protein drink with leucine would improve anabolic responses to resistance exercise (RE: 6 × 8 knee-extension repetitions at 75% of 1-RM) in both young and older adults. Groups (n = 9) of young (24 ± 6 y, BMI 23 ± 2 kg m-2) and older men (70 ± 5 y, BMI 25 ± 2 kg m-2) were randomized to either: (i) RE followed by Slim-Fast Optima (SFO 10 g PRO; 24 g CHO) with 4.2 g of leucine (LEU) or, (ii) RE + SFO with 4.2 g of alanine (ALA; isonitrogenous control). Muscle biopsies were taken before, immediately after, and 1, 2 and 4 h after RE and feeding. Muscle protein synthesis (MPS) was measured by incorporation of [1, 2-13C2] leucine into myofibrillar proteins and the phosphorylation of p70S6K1 by immunoblotting. In young men, both area under the curve (AUC; FSR 0-4 h P < 0.05) and peak FSR (0.11 vs. 0.08%.h.-1; P < 0.05) were greater in the SFO + LEU than in the SFO + ALA group, after RE. Similarly, in older men, AUC analysis revealed that post-exercise anabolic responses were greater in the SFO + LEU than SFO + ALA group, after RE (AUC; FSR 0-4 h P < 0.05). Irrespective of age, increases in p70S6K1 phosphorylation were evident in response to both SFO + LEU and SFO + ALA, although greater with leucine supplementation than alanine (fold-change 2.2 vs. 3.2; P < 0.05), specifically in the older men. We conclude that addition of Leucine to a sub-maximal PRO bolus improves anabolic responses to RE in young and older men.


Asunto(s)
Bebidas , Proteínas en la Dieta/administración & dosificación , Leucina/administración & dosificación , Proteínas Musculares/biosíntesis , Proteínas Musculares/efectos de los fármacos , Entrenamiento de Fuerza , Adulto , Anciano , Índice de Masa Corporal , Proteínas en la Dieta/sangre , Humanos , Leucina/sangre , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miofibrillas/efectos de los fármacos , Miofibrillas/metabolismo , Fosforilación , Biosíntesis de Proteínas/efectos de los fármacos , Proteína de Suero de Leche/administración & dosificación , Adulto Joven
3.
Diabetes ; 65(4): 840-50, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-26740597

RESUMEN

Insulin resistance is closely related to intramyocellular lipid (IMCL) accumulation, and both are associated with increasing age. It remains to be determined to what extent perturbations in IMCL metabolism are related to the aging process per se. On two separate occasions, whole-body and muscle insulin sensitivity (euglycemic-hyperinsulinemic clamp with 2-deoxyglucose) and fat utilization during 1 h of exercise at 50% VO2max ([U-(13)C]palmitate infusion combined with electron microscopy of IMCL) were determined in young lean (YL), old lean (OL), and old overweight (OO) males. OL displayed IMCL content and insulin sensitivity comparable with those in YL, whereas OO were markedly insulin resistant and had more than twofold greater IMCL in the subsarcolemmal (SSL) region. Indeed, whereas the plasma free fatty acid Ra and Rd were twice those of YL in both OL and OO, SSL area only increased during exercise in OO. Thus, skeletal muscle insulin resistance and lipid accumulation often observed in older individuals are likely due to lifestyle factors rather than inherent aging of skeletal muscle as usually reported. However, age per se appears to cause exacerbated adipose tissue lipolysis, suggesting that strategies to reduce muscle lipid delivery and improve adipose tissue function may be warranted in older overweight individuals.


Asunto(s)
Tejido Adiposo/metabolismo , Envejecimiento/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Lípidos/fisiología , Músculo Esquelético/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Ejercicio Físico/fisiología , Prueba de Esfuerzo , Técnica de Clampeo de la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Sobrepeso/metabolismo , Oxidación-Reducción , Adulto Joven
4.
Diabetes ; 64(9): 3160-71, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26015550

RESUMEN

Obesity is increasing, yet despite the necessity of maintaining muscle mass and function with age, the effect of obesity on muscle protein turnover in older adults remains unknown. Eleven obese (BMI 31.9 ± 1.1 kg · m(-2)) and 15 healthy-weight (BMI 23.4 ± 0.3 kg · m(-2)) older men (55-75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under postabsorptive (hypoinsulinemic-euglycemic clamp) and postprandial (hyperinsulinemic hyperaminoacidemic-euglycemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whereas leg lean mass, strength, and work done during maximal exercise were no different. Under postabsorptive conditions, MPS and LPB were equivalent between groups, whereas insulin and amino acid administration increased MPS in only healthy-weight subjects and was associated with lower leg glucose disposal (LGD) (63%) in obese men. Blunting of MPS in the obese men was offset by an apparent decline in LPB, which was absent in healthy-weight subjects. Lower postprandial LGD in obese subjects and blunting of MPS responses to amino acids suggest that obesity in older adults is associated with diminished muscle metabolic quality. This does not, however, appear to be associated with lower leg lean mass or strength.


Asunto(s)
Tejido Adiposo/metabolismo , Contracción Muscular , Proteínas Musculares/biosíntesis , Músculo Esquelético/metabolismo , Obesidad/metabolismo , ARN Mensajero/metabolismo , Adipoquinas/metabolismo , Anciano , Aminoácidos/farmacología , Atrofia , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/farmacología , Inflamación , Insulina/farmacología , Pierna , Masculino , Persona de Mediana Edad , Proteínas Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Obesidad/genética , Obesidad/inmunología
5.
Am J Physiol Endocrinol Metab ; 306(2): E168-76, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-24280127

RESUMEN

Skeletal muscle anabolism associated with postprandial plasma aminoacidemia and insulinemia is contingent upon amino acids (AA) and insulin crossing the microcirculation-myocyte interface. In this study, we hypothesized that increasing muscle microvascular blood volume (flow) would enhance fed-state anabolic responses in muscle protein turnover. We studied 10 young men (23.2 ± 2.1 yr) under postabsorptive and fed [iv Glamin (∼10 g AA), glucose ∼7.5 mmol/l] conditions. Methacholine was infused into the femoral artery of one leg to determine, via bilateral comparison, the effects of feeding alone vs. feeding plus pharmacological vasodilation. We measured leg blood flow (LBF; femoral artery) by Doppler ultrasound, muscle microvascular blood volume (MBV) by contrast-enhanced ultrasound (CEUS), muscle protein synthesis (MPS) and breakdown (MPB; a-v balance modeling), and net protein balance (NPB) using [1,2-(13)C2]leucine and [(2)H5]phenylalanine tracers via gas chromatography-mass spectrometry (GC-MS). Indexes of anabolic signaling/endothelial activation (e.g., Akt/mTORC1/NOS) were assessed using immunoblotting techniques. Under fed conditions, LBF (+12 ± 5%, P < 0.05), MBV (+25 ± 10%, P < 0.05), and MPS (+129 ± 33%, P < 0.05) increased. Infusion of methacholine further enhanced LBF (+126 ± 12%, P < 0.05) and MBV (+79 ± 30%, P < 0.05). Despite these radically different blood flow conditions, neither increases in MPS in response to feeding (0.04 ± 0.004 vs. 0.08 ± 0.01%/h, P < 0.05) nor improvements in NPB (-4.4 ± 2.4 vs. 16.4 ± 5.7 nmol Phe·100 ml leg(-1)·min(-1), P < 0.05) were affected by methacholine infusion (MPS 0.07 ± 0.01%/h; NPB 24.0 ± 7.7 nmol Phe·100 ml leg(-1)·min(-1)), whereas MPB was unaltered by either feeding or infusion of methacholine. Thus, enhancing LBF/MBV above that occurring naturally with feeding alone does not improve muscle anabolism.


Asunto(s)
Ingestión de Alimentos/fisiología , Pierna/irrigación sanguínea , Cloruro de Metacolina/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Adulto , Aminoácidos/farmacología , Glucemia/análisis , Humanos , Masculino , Microvasos/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Fenilalanina/sangre , Adulto Joven
6.
Am J Clin Nutr ; 96(5): 1064-70, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23034966

RESUMEN

BACKGROUND: Cachexia is a consequence of tumor burden caused by ill-defined catabolic alterations in muscle protein turnover. OBJECTIVE: We aimed to explore the effect of tumor burden and resection on muscle protein turnover in patients with nonmetastatic colorectal cancer (CRC), which is a surgically curable tumor that induces cachexia. DESIGN: We recruited the following 2 groups: patients with CRC [n = 13; mean ± SEM age: 66 ± 3 y; BMI (in kg/m(2)): 27.6 ± 1.1] and matched healthy controls (n = 8; age: 71 ± 2 y; BMI: 26.2 ± 1). Control subjects underwent a single study, whereas CRC patients were studied twice before and ~6 wk after surgical resection to assess muscle protein synthesis (MPS), muscle protein breakdown (MPB), and muscle mass by using dual-energy X-ray absorptiometry. RESULTS: Leg muscle mass was lower in CRC patients than in control subjects (6290 ± 456 compared with 7839 ± 617 g; P < 0.05) and had an additional decline after surgery (5840 ± 456 g; P < 0.001). Although postabsorptive MPS was unaffected, catabolic changes with tumor burden included the complete blunting of postprandial MPS (0.038 ± 0.004%/h in the CRC group compared with 0.065 ± 0.006%/h in the control group; P < 0.01) and a trend toward increased MPB under postabsorptive conditions (P = 0.09). Although surgical resection exacerbated muscle atrophy (-7.2%), catabolic changes in protein metabolism had normalized 6 wk after surgery. The recovery in postprandial MPS after surgery was inversely related to the degree of muscle atrophy (r = 0.65, P < 0.01). CONCLUSIONS: CRC patients display reduced postprandial MPS and a trend toward increased MPB, and tumor resection reverses these derangements. With no effective treatment of cancer cachexia, future therapies directed at preserving muscle mass should concentrate on alleviating proteolysis and enhancing anabolic responses to nutrition before surgery while augmenting muscle anabolism after resection.


Asunto(s)
Adenocarcinoma/metabolismo , Caquexia/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteínas de Neoplasias/metabolismo , Absorciometría de Fotón , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Biopsia , Velocidad del Flujo Sanguíneo/fisiología , Composición Corporal , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Arteria Femoral/fisiología , Perfilación de la Expresión Génica , Humanos , Masculino , Músculo Esquelético/patología , Atrofia Muscular/metabolismo , Carga Tumoral
7.
Am J Clin Nutr ; 90(5): 1343-50, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19740975

RESUMEN

BACKGROUND: Reduced postprandial muscle proteolysis is mainly due to increased insulin availability. Whether rates of proteolysis in response to low physiologic doses of insulin are affected by aging is unknown. OBJECTIVES: We tested the hypothesis that suppression of leg protein breakdown (LPB) by insulin is blunted in older subjects, together with blunted activation of Akt-protein kinase B (PKB). DESIGN: Groups of 8 young [mean (+/-SD) age: 24.5 +/- 1.8 y] and older (65.0 +/- 1.3 y) participants were studied during euglycemic (5 mmol/L), isoaminoacidemic (blood leucine approximately 120 micromol/L) clamp procedures at plasma insulin concentrations of approximately 5 and approximately 15 microIU/mL for 1.5 h. Leg amino acid balance, whole-leg protein turnover (as dilution of amino acid tracers), and muscle protein synthesis were measured with D(5)-phenylalanine and [1,2-(13)C(2)]leucine. The kinase activity of muscle Akt-PKB and the extent of phosphorylation of signaling proteins associated with the mTOR (mammalian target of rapamycin) pathway were measured before and after the clamp procedures. RESULTS: Basal LPB rates were not different between groups (66 +/- 11 compared with 51 +/- 10 nmol leucine x 100 mL leg(-1) x min(-1) and 30 +/- 5 compared with 24 +/- 4 nmol phenylalanine x 100 mL leg(-1) x min(-1) in young and older groups, respectively). However, although insulin at approximately 15 microIU/mL lowered LPB by 47% in the young subjects (P < 0.05) and abolished the negative leg amino acid balance, this caused only a 12% fall (P > 0.05) in the older group. Akt-PKB activity mirrored decreases in LPB. No differences were seen in muscle protein synthesis or associated anabolic signaling phosphoproteins. CONCLUSIONS: At moderate availability, the effect of insulin on LPB is diminished in older human beings, and this effect may be mediated through blunted Akt-PKB activation.


Asunto(s)
Insulina/farmacología , Enfermedades Musculares/prevención & control , Adulto , Anciano , Envejecimiento/fisiología , Aminoácidos/sangre , Aminoácidos/metabolismo , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Pierna , Leucina/metabolismo , Masculino , Proteínas Musculares/efectos de los fármacos , Proteínas Musculares/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo
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