Pablo M Garcia-Roves - Academia.edu (original) (raw)

Papers by Pablo M Garcia-Roves

Research paper thumbnail of UCP3 deficiency increases cardiac ischemia-reperfusion injury: effects on energy metabolism, mitochondrial structure and oxidative stress

Free Radical Biology and Medicine, May 1, 2023

Research paper thumbnail of ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis

Journal of Hepatology, Nov 1, 2014

Background & Aim-Acid sphingomyelinase (ASMase) is activated in nonalcoholic steatohepatitis (NAS... more Background & Aim-Acid sphingomyelinase (ASMase) is activated in nonalcoholic steatohepatitis (NASH). However, ASMase's contribution to NASH is poorly understood and

Research paper thumbnail of Generating reference values on mitochondrial respiration in permeabilized muscle fibers

Permeabilized muscle fibers (pfi) are widely used to assess mitochondrial (mt) respiratory functi... more Permeabilized muscle fibers (pfi) are widely used to assess mitochondrial (mt) respiratory function in skeletal muscle of various models in different physiological and pathological conditions. Facing the numerous data available for mt-respiration from the literature, it remains challenging to determine what the right values are for a specific respiratory protocol. Moreover, mt-respiration values are highly dependent on pfi preparation, which required good technical skills. In the frame of COST Action MITOEAGLE, one of the objectives of WG2 is the generation of reference values for mitochondrial respirometry in permeabilized skeletal muscle sample preparations. The idea is that new researchers in the field follow a reference protocol and check if their values are in an acceptable range. This approach could serve to test researchers' technical skills and therefore determine if they are proficient enough to perform their own experiments with confidence.

Research paper thumbnail of Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Cells, 2019

Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availabili... more Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca2+/ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the meta...

Research paper thumbnail of Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1α-Dependent Transcriptional Program

iScience, 2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bo... more Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process that remains poorly defined. Here, we show that restriction in glucose supply promotes the osteocyte transcriptional program while also being associated with increased mitochondrial DNA levels. Glucose deprivation triggered the activation of the AMPK/PGC-1 pathway. AMPK and SIRT1 activators or PGC-1a overexpression are sufficient to enhance osteocyte gene expression in IDG-SW3 cells, murine primary osteoblasts, osteocytes, and organotypic/ex vivo bone cultures. Conversely, osteoblasts and osteocytes deficient in Ppargc1a and b were refractory to the effects of glucose restriction. Finally, conditional ablation of both genes in osteoblasts and osteocytes generate osteopenia and reduce osteocytic gene expression in mice. Altogether, we uncovered a role for PGC-1 in the regulation of osteocyte gene expression.

Research paper thumbnail of Mitochondrial respiratory states and rates: building blocks of mitochondrial physiology

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2018

This manuscript on 'Mitochondrial respiratory states and rates' is a position statement in the fr... more This manuscript on 'Mitochondrial respiratory states and rates' is a position statement in the frame of COST Action CA15203 MitoEAGLE. The list of co-authors evolved beyond phase 1 (phase 1 versions 1-44) in the bottom-up spirit of COST. This is an open invitation to scientists and students to join as co-authors, to provide a balanced view on mitochondrial respiratory control, a fundamental introductory presentation of the concept of the protonmotive force, and a consensus statement on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Phase 2: MitoEAGLE preprint 'The protonmotive force and respiratory control' (Versions 01-21): We continue to invite comments and suggestions, particularly if you are an early career investigator adding an open future-oriented perspective, or an established scientist providing a balanced historical basis. Your critical input into the quality of the manuscript will be most welcome, improving our aims to be educational, general, consensusoriented, and practically helpful for students working in mitochondrial respiratory physiology.

Research paper thumbnail of Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

Redox Biology, 2017

Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations... more Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

Research paper thumbnail of The disruption of mitochondrial axonal transport is an early event in neuroinflammation

Journal of neuroinflammation, Jan 28, 2015

In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade th... more In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons. Mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenos...

Research paper thumbnail of High‐Resolution Respirometry for Mitochondrial Characterization of Ex Vivo Mouse Tissues

Current Protocols in Mouse Biology, 2015

This article describes methodologies to examine mitochondrial respiration in fresh preparations o... more This article describes methodologies to examine mitochondrial respiration in fresh preparations of mouse tissues, including skeletal muscle, heart, liver, white and brown adipose tissue, and brain. Reference values and tips to maximize experimental efficiencies are also provided. Finally, correction methods and complementary techniques to properly interpret the results are presented and contrasted. © 2015 by John Wiley & Sons, Inc.

Research paper thumbnail of Exercise-beyond skeletal muscle energy metabolism

Journal of applied physiology (Bethesda, Md. : 1985), 2010

Research paper thumbnail of Skeletal Muscle - From Myogenesis to Clinical Relations

Research paper thumbnail of P.1.011 Evidence of hypothalamic mitochondrial dysfunction and neurodegeneration in the anorectic anx/anx mouse model

European Neuropsychopharmacology, 2011

Research paper thumbnail of Post-exercise vitamin C supplementation and recovery from demanding exercise

European Journal of Applied Physiology, 2003

The aim of this study was to investigate whether post-exercise vitamin C supplementation influenc... more The aim of this study was to investigate whether post-exercise vitamin C supplementation influences recovery from an unaccustomed bout of exercise. Sixteen male subjects were allocated to either a placebo (P; n=8) or vitamin C (VC) group ( n=8). Subjects performed a prolonged (90-min) intermittent shuttle-running test, and supplementation began after the cessation of exercise. Immediately after exercise the VC group consumed 200 mg of VC dissolved in a 500 ml drink, whereas the subjects in the P group consumed the drink alone. Later on the same day and then in the morning and evening of the following 2 days, subjects consumed additional identical drinks. Plasma VC concentrations in the VC group increased above those in the P group 1 h after exercise and remained above P values for the 3 days after exercise. Nevertheless, post-exercise VC supplementation was not associated with improved recovery. Post-exercise serum creatine kinase activities and myoglobin concentrations were unaffected by supplementation. Muscle soreness and the recovery of muscle function in the leg flexors and extensors were not different in VC and P groups. Furthermore, although plasma concentrations of interleukin-6 and malondialdehyde increased following exercise, there was no difference between VC and P groups. These results suggest that either free radicals are not involved in delaying the recovery process following a bout of unaccustomed exercise, or that the consumption of VC wholly after exercise is unable to deliver this antioxidant to the appropriate sites with sufficient expediency to improve recovery.

Research paper thumbnail of Diabetes mellitus and metabolic syndrome

Clinical Chemistry and Laboratory Medicine, 2011

Research paper thumbnail of Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase

Biochemical Journal, 2011

Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurod... more Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual-specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Previously, we and others showed that laforin and malin form a functional complex that regulates multiple aspects of glycogen metabolism, and that the interaction between laforin and malin is enhanced by conditions activating AMPK (AMP-activated protein kinase). In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser25 as the residue involved in this modification. We also show that Ser25 is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously establishe...

Research paper thumbnail of Impact of GLP-1 receptor agonist versus omega-3 fatty acids supplement on obesity-induced alterations of mitochondrial respiration

Frontiers in Endocrinology, Mar 23, 2023

Research paper thumbnail of Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Redox Biology

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to di... more Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a com- bined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue

Research paper thumbnail of selected for high and low body weight influenced by a cis-acting eQTL in two chicken lines Expression of carnitine palmitoyl-CoA transferase-1B is

Research paper thumbnail of Obesity causes irreversible mitochondria failure in visceral adipose tissue despite successful anti-obesogenic lifestyle-based interventions

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to di... more Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most pathological features were successfully reverted, we observed a high degree of metabolic dysfunction irreversibility in visceral white adipose tissue, characterised by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and apparent global phenotypic recovery, obesity specifically triggered in visceral adipose a cascade of events progressing from mitochondrial metabolic and proteostatic defects to widespread cellular stress, which compromises its biosynthetic and recycling capacity. Our data indicate that obesity prompts a lasting metabolic fingerprint that leads...

Research paper thumbnail of Adipose tissue mitochondrial dysfunction in human obesity is linked to a specific DNA methylation signature in adipose-derived stem cells

International Journal of Obesity, 2018

Background A functional population of adipocyte precursors, termed adipose-derived stromal/stem c... more Background A functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs. Methods Using epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss-and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals. Results We found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number. Conclusions We identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes.

Research paper thumbnail of UCP3 deficiency increases cardiac ischemia-reperfusion injury: effects on energy metabolism, mitochondrial structure and oxidative stress

Free Radical Biology and Medicine, May 1, 2023

Research paper thumbnail of ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis

Journal of Hepatology, Nov 1, 2014

Background & Aim-Acid sphingomyelinase (ASMase) is activated in nonalcoholic steatohepatitis (NAS... more Background & Aim-Acid sphingomyelinase (ASMase) is activated in nonalcoholic steatohepatitis (NASH). However, ASMase's contribution to NASH is poorly understood and

Research paper thumbnail of Generating reference values on mitochondrial respiration in permeabilized muscle fibers

Permeabilized muscle fibers (pfi) are widely used to assess mitochondrial (mt) respiratory functi... more Permeabilized muscle fibers (pfi) are widely used to assess mitochondrial (mt) respiratory function in skeletal muscle of various models in different physiological and pathological conditions. Facing the numerous data available for mt-respiration from the literature, it remains challenging to determine what the right values are for a specific respiratory protocol. Moreover, mt-respiration values are highly dependent on pfi preparation, which required good technical skills. In the frame of COST Action MITOEAGLE, one of the objectives of WG2 is the generation of reference values for mitochondrial respirometry in permeabilized skeletal muscle sample preparations. The idea is that new researchers in the field follow a reference protocol and check if their values are in an acceptable range. This approach could serve to test researchers' technical skills and therefore determine if they are proficient enough to perform their own experiments with confidence.

Research paper thumbnail of Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Cells, 2019

Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availabili... more Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca2+/ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the meta...

Research paper thumbnail of Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1α-Dependent Transcriptional Program

iScience, 2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bo... more Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process that remains poorly defined. Here, we show that restriction in glucose supply promotes the osteocyte transcriptional program while also being associated with increased mitochondrial DNA levels. Glucose deprivation triggered the activation of the AMPK/PGC-1 pathway. AMPK and SIRT1 activators or PGC-1a overexpression are sufficient to enhance osteocyte gene expression in IDG-SW3 cells, murine primary osteoblasts, osteocytes, and organotypic/ex vivo bone cultures. Conversely, osteoblasts and osteocytes deficient in Ppargc1a and b were refractory to the effects of glucose restriction. Finally, conditional ablation of both genes in osteoblasts and osteocytes generate osteopenia and reduce osteocytic gene expression in mice. Altogether, we uncovered a role for PGC-1 in the regulation of osteocyte gene expression.

Research paper thumbnail of Mitochondrial respiratory states and rates: building blocks of mitochondrial physiology

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2018

This manuscript on 'Mitochondrial respiratory states and rates' is a position statement in the fr... more This manuscript on 'Mitochondrial respiratory states and rates' is a position statement in the frame of COST Action CA15203 MitoEAGLE. The list of co-authors evolved beyond phase 1 (phase 1 versions 1-44) in the bottom-up spirit of COST. This is an open invitation to scientists and students to join as co-authors, to provide a balanced view on mitochondrial respiratory control, a fundamental introductory presentation of the concept of the protonmotive force, and a consensus statement on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Phase 2: MitoEAGLE preprint 'The protonmotive force and respiratory control' (Versions 01-21): We continue to invite comments and suggestions, particularly if you are an early career investigator adding an open future-oriented perspective, or an established scientist providing a balanced historical basis. Your critical input into the quality of the manuscript will be most welcome, improving our aims to be educational, general, consensusoriented, and practically helpful for students working in mitochondrial respiratory physiology.

Research paper thumbnail of Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

Redox Biology, 2017

Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations... more Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

Research paper thumbnail of The disruption of mitochondrial axonal transport is an early event in neuroinflammation

Journal of neuroinflammation, Jan 28, 2015

In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade th... more In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons. Mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenos...

Research paper thumbnail of High‐Resolution Respirometry for Mitochondrial Characterization of Ex Vivo Mouse Tissues

Current Protocols in Mouse Biology, 2015

This article describes methodologies to examine mitochondrial respiration in fresh preparations o... more This article describes methodologies to examine mitochondrial respiration in fresh preparations of mouse tissues, including skeletal muscle, heart, liver, white and brown adipose tissue, and brain. Reference values and tips to maximize experimental efficiencies are also provided. Finally, correction methods and complementary techniques to properly interpret the results are presented and contrasted. © 2015 by John Wiley & Sons, Inc.

Research paper thumbnail of Exercise-beyond skeletal muscle energy metabolism

Journal of applied physiology (Bethesda, Md. : 1985), 2010

Research paper thumbnail of Skeletal Muscle - From Myogenesis to Clinical Relations

Research paper thumbnail of P.1.011 Evidence of hypothalamic mitochondrial dysfunction and neurodegeneration in the anorectic anx/anx mouse model

European Neuropsychopharmacology, 2011

Research paper thumbnail of Post-exercise vitamin C supplementation and recovery from demanding exercise

European Journal of Applied Physiology, 2003

The aim of this study was to investigate whether post-exercise vitamin C supplementation influenc... more The aim of this study was to investigate whether post-exercise vitamin C supplementation influences recovery from an unaccustomed bout of exercise. Sixteen male subjects were allocated to either a placebo (P; n=8) or vitamin C (VC) group ( n=8). Subjects performed a prolonged (90-min) intermittent shuttle-running test, and supplementation began after the cessation of exercise. Immediately after exercise the VC group consumed 200 mg of VC dissolved in a 500 ml drink, whereas the subjects in the P group consumed the drink alone. Later on the same day and then in the morning and evening of the following 2 days, subjects consumed additional identical drinks. Plasma VC concentrations in the VC group increased above those in the P group 1 h after exercise and remained above P values for the 3 days after exercise. Nevertheless, post-exercise VC supplementation was not associated with improved recovery. Post-exercise serum creatine kinase activities and myoglobin concentrations were unaffected by supplementation. Muscle soreness and the recovery of muscle function in the leg flexors and extensors were not different in VC and P groups. Furthermore, although plasma concentrations of interleukin-6 and malondialdehyde increased following exercise, there was no difference between VC and P groups. These results suggest that either free radicals are not involved in delaying the recovery process following a bout of unaccustomed exercise, or that the consumption of VC wholly after exercise is unable to deliver this antioxidant to the appropriate sites with sufficient expediency to improve recovery.

Research paper thumbnail of Diabetes mellitus and metabolic syndrome

Clinical Chemistry and Laboratory Medicine, 2011

Research paper thumbnail of Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase

Biochemical Journal, 2011

Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurod... more Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual-specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Previously, we and others showed that laforin and malin form a functional complex that regulates multiple aspects of glycogen metabolism, and that the interaction between laforin and malin is enhanced by conditions activating AMPK (AMP-activated protein kinase). In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser25 as the residue involved in this modification. We also show that Ser25 is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously establishe...

Research paper thumbnail of Impact of GLP-1 receptor agonist versus omega-3 fatty acids supplement on obesity-induced alterations of mitochondrial respiration

Frontiers in Endocrinology, Mar 23, 2023

Research paper thumbnail of Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Redox Biology

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to di... more Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a com- bined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue

Research paper thumbnail of selected for high and low body weight influenced by a cis-acting eQTL in two chicken lines Expression of carnitine palmitoyl-CoA transferase-1B is

Research paper thumbnail of Obesity causes irreversible mitochondria failure in visceral adipose tissue despite successful anti-obesogenic lifestyle-based interventions

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to di... more Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most pathological features were successfully reverted, we observed a high degree of metabolic dysfunction irreversibility in visceral white adipose tissue, characterised by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and apparent global phenotypic recovery, obesity specifically triggered in visceral adipose a cascade of events progressing from mitochondrial metabolic and proteostatic defects to widespread cellular stress, which compromises its biosynthetic and recycling capacity. Our data indicate that obesity prompts a lasting metabolic fingerprint that leads...

Research paper thumbnail of Adipose tissue mitochondrial dysfunction in human obesity is linked to a specific DNA methylation signature in adipose-derived stem cells

International Journal of Obesity, 2018

Background A functional population of adipocyte precursors, termed adipose-derived stromal/stem c... more Background A functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs. Methods Using epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss-and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals. Results We found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number. Conclusions We identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes.