RESUMEN
BACKGROUND: Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy. METHODS: We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level. RESULTS: The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8). CONCLUSIONS: Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Asunto(s)
Glucosa , Músculo Esquelético , Glucosa/metabolismo , Músculo Esquelético/metabolismo , Animales , Ratones , Humanos , Hipertrofia , Fibras Musculares Esqueléticas/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Metabolómica/métodosRESUMEN
Caloric restriction (CR) is of key importance in combating obesity and its associated diseases. We aimed to examine effects of dietary macronutrient distribution on weight loss and metabolic health in obese mice exposed to CR. Male C57BL/6J mice underwent diet-induced obesity for 18 weeks. Thereafter mice were exposed to a 6-week CR for up to 40% on either low-fat diet (LFD; 20, 60, 20% kcal from protein, carbohydrate, fat), low-carb diet (LCD; 20, 20, 60% kcal, respectively) or high-pro diet (HPD; 35, 35, 30% kcal, respectively) (n = 16 each). Ten mice on the obesogenic diet served as age-matched controls. Body composition was evaluated by tissue dissections. Glucose tolerance, bloods lipids and energy metabolism were measured. CR-induced weight loss was similar for LFD and LCD while HPD was associated with a greater weight loss than LCD. The diet groups did not differ from obese controls in hindlimb muscle mass, but showed a substantial decrease in body fat without differences between them. Glucose tolerance and blood total cholesterol were weight-loss dependent and mostly improved in LFD and HPD groups during CR. Blood triacylglycerol was lowered only in LCD group compared to obese controls. Thus, CR rather than macronutrient distribution in the diet plays the major role for improvements in body composition and glucose control in obese mice. Low-carbohydrate-high-fat diet more successfully reduces triacylglycerol but not cholesterol levels compared to isocaloric high-carbohydrate-low-fat weight loss diets.
Asunto(s)
Tejido Adiposo/metabolismo , Glucemia/metabolismo , Composición Corporal , Restricción Calórica , Dieta , Nutrientes/administración & dosificación , Obesidad/terapia , Animales , Colesterol/sangre , Dieta Baja en Carbohidratos , Dieta con Restricción de Grasas , Dieta Alta en Grasa , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Metabolismo Energético , Intolerancia a la Glucosa/prevención & control , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Músculos/metabolismo , Triglicéridos/sangre , Pérdida de PesoRESUMEN
OBJECTIVE: It is controversial whether low-carbohydrate diets are better suited for weight control and metabolic health than high-carbohydrate diets. This study examined whether these diets induce different improvements in body composition and glucose tolerance in obese mice during caloric restriction (CR). METHODS: Male C57BL/6J mice were fed an obesogenic diet ad libitum for 18 weeks and then subjected to 6-week progressive CR of up to 40%, using either a low-fat or low-carbohydrate diet with equal protein content. Mice fed a regular chow diet ad libitum served as controls. Body mass, hindlimb muscle mass, fat mass, energy expenditure, and glucose tolerance were compared between the groups. RESULTS: Initially low-fat and low-carbohydrate groups had similar body mass, which was 30% greater compared with controls. CR induced similar weight loss in low-fat and low-carbohydrate groups. This weight loss was mainly due to fat loss in both groups. Energy expenditure of freely moving mice did not differ between the groups. Glucose tolerance improved compared with the values before CR and in controls but did not differ between the diets. CONCLUSIONS: Dietary carbohydrate or fat content does not affect improvements in body composition and metabolic health in obese mice exposed to CR with fixed energy and protein intake.