A physical model of cell metabolism

Cell metabolism is characterized by three fundamental energy demands: to sustain cell maintenance, to trigger aerobic fermentation and to achieve maximum metabolic rate. The transition to aerobic fermentation and the maximum metabolic rate are currently understood based on enzymatic cost constraints. Yet, we are lacking a theory explaining the maintenance energy demand. Here we report a physical model of cell metabolism that explains the origin of these three energy scales. Our key hypothesis is that the maintenance energy demand is rooted on the energy expended by molecular motors to fluidize the cytoplasm and counteract molecular crowding. Using this model and independent parameter estimates we make predictions for the three energy scales that are in quantitative agreement with experimental values. The model also recapitulates the dependencies of cell growth with extracellular osmolarity and temperature. This theory brings together biophysics and cell biology in a tractable model that can be applied to understand key principles of cell metabolism

Characterizing steady states of genome-scale metabolic networks in continuous cell cultures

We present a model for continuous cell culture coupling intra-cellular metabolism to extracellular variables describing the state of the bioreactor, taking into account the growth capacity of the cell and the impact of toxic byproduct accumulation. We provide a method to determine the steady states of this system that is tractable for metabolic networks of arbitrary complexity. We demonstrate our approach in a toy model first, and then in a genome-scale metabolic network of the Chinese hamster ovary cell line, obtaining results that are in qualitative agreement with experimental observations. More importantly, we derive a number of consequences from the model that are independent of parameter values. First, that the ratio between cell density and dilution rate is an ideal control parameter to fix a steady state with desired metabolic properties invariant across perfusion systems. This conclusion is robust even in the presence of multi-stability, which is explained in our model by the negative feedback loop on cell growth due to toxic byproduct accumulation. Moreover, a complex landscape of steady states in continuous cell culture emerges from our simulations, including multiple metabolic switches, which also explain why cell-line and media benchmarks carried out in batch culture cannot be extrapolated to perfusion. On the other hand, we predict invariance laws between continuous cell cultures with different parameters. A practical consequence is that the chemostat is an ideal experimental model for large-scale high-density perfusion cultures, where the complex landscape of metabolic transitions is faithfully reproduced. Thus, in order to actually reflect the expected behavior in perfusion, performance benchmarks of cell-lines and culture media should be carried out in a chemostat

Limits of aerobic metabolism in cancer cells

Cancer cells exhibit high rates of glycolysis and glutaminolysis. Glycolysis can provide energy and glutaminolysis can provide carbon for anaplerosis and reductive carboxylation to citrate. However, all these metabolic requirements could be in principle satisfied from glucose. Here we investigate why cancer cells do not satisfy their metabolic demands using aerobic biosynthesis from glucose. Based on the typical composition of a mammalian cell we quantify the energy demand and the OxPhos burden of cell biosynthesis from glucose. Our calculation demonstrates that aerobic growth from glucose is feasible up to a minimum doubling time that is proportional to the OxPhos burden and inversely proportional to the mitochondria OxPhos capacity. To grow faster cancer cells must activate aerobic glycolysis for energy generation and uncouple NADH generation from biosynthesis. To uncouple biosynthesis from NADH generation cancer cells can synthesize lipids from carbon sources that do not produce NADH in their catabolism, including acetate and the amino acids glutamate, glutamine, phenylalanine and tyrosine. Finally, we show that cancer cell lines have an OxPhos capacity that is insufficient to support aerobic biosynthesis from glucose. We conclude that selection for high rate of biosynthesis implies a selection for aerobic glycolysis and uncoupling biosynthesis from NADH generation

Effects of supplementation of L-carnitine on the body composition of trained and sedentary rats

El objetivo del presente estudio es determinar el efecto de la suplementación de L-carnitina sobre la composición corporal de ratas entrenadas y sedentarias. Fueron seleccionadas de forma aleatoria 30 ratas machos Wistar, de 12 semanas de vida, cuyo peso osciló entre 350 a 380 gramos, constituyéndose cuatro grupos de animales: sedentario no suplementado (SNS), sedentario suplementado (SS), entrenado no suplementado (ENS) y entrenado suplementado (ES). El entrenamiento fue realizado con sesiones de carrera en la estera rodante, con duración de una hora y con suplementación oral crónica de L-Carnitina. Ambos protocolos con una duración de 4 semanas. La composición corporal fue evaluada a través de ecuaciones de predicción para determinar la masa libre de grasa (MLG) y masa de grasa (MG). Los resultados muestran que el entrenamiento físico disminuye los valores de la MLG y MG en el grupo ENS, y que la administración de la L-carnitina en forma conjunta con el entrenamiento físico revierte parcialmente la reducción de la MLG en el grupo ES. Finalmente se concluye que el ejercicio físico debe ser realizado juntamente con la suplementación de L-carnitina, permitiendo una disminución de la MG y mantener los niveles de MLG en ratas en proceso de crecimiento.The aim of this study is to determine the effect of L-carnitine supplementation on body composition of trained and sedentary rats. Were randomly selected 30 male Wistar rats of 12 weeks of age, whose weight ranged between 350 to 380 grams, four groups of animals: sedentary non-supplemented (SNS), sedentary supplemented (SS), trained not supplemented (ENS) trained and supplemented (ES). The training was done with sessions running on a treadmill, lasting an hour and chronic oral supplementation of L-carnitine. Both protocols with a duration of 4 weeks. Body composition was assessed by prediction equations to determine fat-free (FFM) and fat mass (FM). The results show that physical training decreases the values of FFM and FM in the ENS group, and that the administration of L-carnitine together with physical training partially reverses the reduction of MLG in ES. Finally concluded that physical exercise should be conducted jointly with the supplementation of L-carnitine, allowing a reduction in the MG and maintain levels in rats MLG growth process.Peer Reviewe

Correlation between explosive strength and speed in young players

El objetivo del presente estudio fue determinar las relaciones entre la fuerza explosiva y la velocidad V(20m) en futbolistas cadetes y juveniles. Para el estudio fueron evaluados 18 jugadores de la categoría infantil y 18 de la categoría juvenil, siendo un total de 36 futbolistas. Se evaluó el peso corporal (kg), estatura (cm) y el % de grasa corporal. Así como también los test de squat Jump SJ(cm), CounterMovement Jump CMJ(cm) y saltos verticales contínuos en 5 segundos CJ5s(cm). Los resultados muestran altas correlaciones entre SJ y CMJ (0,80), SJ y V(20m) ( 0,71) y CMJ y V(20m) (-0,61) en cadetes, así como en juveniles SJ y CMJ (0,89) y SJ y V(20m) (-0,62), respectivamente. Por lo tanto, se concluye que la fuerza explosiva se encuentra en estrecha relación con la velocidad (20m), tanto en jugadores de la categoría cadetes y juvenil.The aim of this study was to determine the relationship between the explosive power and speed V(20m) in children and youth players. For the study were evaluated 18 players in the cadet’s category and 18 in the youth category, for a total of 36 players. We assessed body weight (kg), height (cm) and% body fat, as well as the squat jump test, SJ (cm), countermovement jump CMJ (cm) and continuous vertical jumps in 5 seconds CJ5s (cm). The results show high correlations between SJ and CMJ (0.80), SJ and V(20m) ( 0.71) and CMJ and V (20m) (-0.61) in cadet’s and youth in SJ and CMJ (0.89) and SJ and V(20m) (-0.62), respectively. Therefore, we conclude that the explosive force is closely related to the speed (20m), both players of the cadets and youth category.Peer Reviewe

Propuesta de valores normativos para la clasificación de variables antropométricas en futbolistas profesionales

El objetivo del presente estudio es proponer una clasificación para identificar el % graso ideal a partir de variables antropométricas en futbolistas profesionales. Para lo cual, fueron utilizados 132 futbolistas profesionales a los que se les evaluó la Masa corporal (kg), Estatura (cm) y pliegues cutáneos (mm). Para el análisis estadístico se utilizó la estadística descriptiva de media aritmética (X), desviación estándar (DE), coeficiente de variación (CV) y para clasificar las variables antropométricas se utilizó los percentiles. Los resultados muestran que los valores ideales de % graso de los futbolistas oscila entre 9,0 a 12,6%, (p25 a p75), respectivamente. Finalmente, los parámetros adoptados como puntos de corte podrían ser utilizados como posibles indicadores para diagnosticar futbolistas con riesgo de lesión (pp75), a partir del % graso, masa corporal, e inclusive por la sumatoria de cuatro y seis pliegues cutáneos.The aim of this study is to propose a classification to identify the ideal % fat from anthropometric variables in professional soccer players. To which, using 132 players were professionals who were assessed for body mass (kg) Height (cm) and skinfolds (mm). For statistical analysis, descriptive statistics were used for arithmetic mean (X), standard deviation (SD), coefficient of variation (CV) and to classify the variables used anthropometric percentiles. The results show that the ideal values of % fat of the players ranges from 9.0 to 12.6% (p25 to p75), respectively. Finally, the parameters adopted as cutoff points could be used as indicators to diagnose potential players at risk of injury (p p75) from the % fat, body mass, and even by the sum of four and six skinfolds.Peer Reviewe

Extracellular Vesicles in Hepatobiliary Malignancies

Primary hepatobiliary malignancies include a heterogeneous group of cancers with dismal prognosis, among which hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatoblastoma (HB) stand out. These tumors mainly arise from the malignant transformation of hepatocytes, cholangiocytes (bile duct epithelial cells) or hepatoblasts (embryonic liver progenitor cells), respectively. Early diagnosis, prognosis prediction and effective therapies are still a utopia for these diseases. Extracellular vesicles (EVs) are small membrane-enclosed spheres secreted by cells and present in biological fluids. They contain multiple types of biomolecules, such as proteins, RNA, DNA, metabolites and lipids, which make them a potential source of biomarkers as well as regulators of human pathobiology. In this review, the role of EVs in the pathogenesis of hepatobiliary cancers and their potential usefulness as disease biomarkers are highlighted. Moreover, the therapeutic value of EV regulation is discussed and future directions on basic and clinical research are indicated.Spanish Ministries of Economy and Competitiveness [JB (FIS PI12/00380, FIS PI15/01132 and Miguel Servet Programme CON14/00129); MP (FIS PI14/00399, FIS PI17/00022) and Ramon y Cajal Programme RYC-2015-17755] cofinanced by Fondo Europeo de Desarrollo Regional (FEDER); ISCIII [CIBERehd: JB, LB, and MP], Spain; Diputacion Foral Gipuzkoa (JB: DFG15/010, DFG16/004), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to JB); Department of Health of the Basque Country (JB: 2013111173 and 2017111010; MP: 2015111100), and AECC Scientific Foundation (JB). AL and PO were funded by the Basque Government