lionel tintignac | University of Basel, University Hospital (original) (raw)

Papers by lionel tintignac

Cancer research, Mar 22, 2024

Research Square (Research Square), Feb 12, 2020

Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-t... more Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-term disability and higher mortality. Bolus nutrition (30-60 min period), while having a similar incidence of aspiration as continuous feeding, seems to provide metabolic benefits through increased muscle protein synthesis due to higher leucine peaks. To date, clinical evidence on achievement of nutritional goals and influence of bolus nutrition on skeletal muscle metabolism in ICU patients is lacking. The aim of the Pro BoNo study (Protein Bolus Nutrition) is to compare intermittent and continuous enteral feeding with a specific highprotein formula. We hypothesise that target quantity of protein is reached earlier (within 36 hours) by an intermittent feeding protocol with a favourable influence on muscle protein synthesis. Methods Pro BoNo is a prospective randomised controlled study aiming to compare the impact of intermittent and continuous enteral feeding on preventing muscle wasting in 60 critically ill patients recruited during the first 48 hours after ICU admission. The primary outcome measure is the time until the daily protein target (≥1.5 g protein/kg bodyweight/24h) is achieved. Secondary outcome measures include tolerance of enteral feeding and trajectory of glucose, urea and IGF-1. Ultrasound and muscle biopsy of the quadriceps will be performed. Discussion The Basel Pro BoNo study aims to collect innovative data on the effect of intermittent enteral feeding of critically ill patients on muscle wasting.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Oct 23, 2012

PLOS ONE, Dec 9, 2014

Western-blot analyses of Myogenin, MyoD, Sirt1 and Tubulin in C2C12-LucshRNA (shCTL) and... more Western-blot analyses of Myogenin, MyoD, Sirt1 and Tubulin in C2C12-LucshRNA (shCTL) and C2C12-SIRT3shRNA (shSIRT3) cells at the indicated states (Proliferation, P; Cell Confluence, C and 3 days after the induction of differentiation D3). Results are normalized relatively to Tubulin protein levels and expressed as the mean ± SD of three separate experiments. ANOVA main effect: ## P<0.01, ### P<0.001 vs. shCTL cells. Post-hoc significance: *P<0.05, **P<0.01 and ***P<0.001 vs. proliferating myoblasts for each cell type. §P<0.05, §§P<0.01 and §§§ P<0.001 vs. shCTL cells at the same stage.</p

HAL (Le Centre pour la Communication Scientifique Directe), Sep 26, 2012

Research Square (Research Square), Jul 15, 2020

Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-t... more Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-term disability and higher mortality. Bolus nutrition (30-60 min period), while having a similar incidence of aspiration as continuous feeding, seems to provide metabolic bene ts through increased muscle protein synthesis due to higher leucine peaks. To date, clinical evidence on achievement of nutritional goals and in uence of bolus nutrition on skeletal muscle metabolism in ICU patients is lacking. The aim of the Pro BoNo study (Protein Bolus Nutrition) is to compare intermittent and continuous enteral feeding with a speci c highprotein formula. We hypothesise that target quantity of protein is reached earlier (within 36 hours) by an intermittent feeding protocol with a favourable in uence on muscle protein synthesis. Methods Pro BoNo is a prospective randomised controlled study aiming to compare the impact of intermittent and continuous enteral feeding on preventing muscle wasting in 60 critically ill patients recruited during the rst 48 hours after ICU admission. The primary outcome measure is the time until the daily protein target (≥1.5 g protein/kg bodyweight/24h) is achieved. Secondary outcome measures include tolerance of enteral feeding and evolution of glucose, urea and IGF-1. Ultrasound and muscle biopsy of the quadriceps will be performed. Discussion The Basel Pro BoNo study aims to collect innovative data on the effect of intermittent enteral feeding of critically ill patients on muscle wasting.

BMC Biology, Jul 3, 2020

Background: mTOR signaling is an essential nutrient and energetic sensing pathway. Here we descri... more Background: mTOR signaling is an essential nutrient and energetic sensing pathway. Here we describe AIMTOR, a sensitive genetically encoded BRET (Bioluminescent Resonance Energy Transfer) biosensor to study mTOR activity in living cells. Results: As a proof of principle, we show in both cell lines and primary cell cultures that AIMTOR BRET intensities are modified by mTOR activity changes induced by specific inhibitors and activators of mTORC1 including amino acids and insulin. We further engineered several versions of AIMTOR enabling subcellular-specific assessment of mTOR activities. We then used AIMTOR to decipher mTOR signaling in physio-pathological conditions. First, we show that mTORC1 activity increases during muscle cell differentiation and in response to leucine stimulation in different subcellular compartments such as the cytosol and at the surface of the lysosome, the nucleus, and near the mitochondria. Second, in hippocampal neurons, we found that the enhancement of neuronal activity increases mTOR signaling. AIMTOR further reveals mTOR-signaling dysfunctions in neurons from mouse models of autism spectrum disorder. Conclusions: Altogether, our results demonstrate that AIMTOR is a sensitive and specific tool to investigate mTORsignaling dynamics in living cells and phenotype mTORopathies.

PLOS ONE, Dec 9, 2014

Sirtuin 3 (SIRT3), one of the seven mammalian sirtuins, is a mitochondrial NAD +dependent deacety... more Sirtuin 3 (SIRT3), one of the seven mammalian sirtuins, is a mitochondrial NAD +dependent deacetylase known to control key metabolic pathways. SIRT3 deacetylases and activates a large number of mitochondrial enzymes involved in the respiratory chain, in ATP production, and in both the citric acid and urea cycles. We have previously shown that the regulation of myoblast differentiation is tightly linked to mitochondrial activity. Since SIRT3 modulates mitochondrial activity, we decide to address its role during myoblast differentiation. For this purpose, we first investigated the expression of endogenous SIRT3 during C2C12 myoblast differentiation. We further studied the impact of SIRT3 silencing on both the myogenic potential and the mitochondrial activity of C2C12 cells. We showed that SIRT3 protein expression peaked at the onset of myoblast differentiation. The inhibition of SIRT3 expression mediated by the stable integration of SIRT3 short inhibitory RNA (SIRT3shRNA) in C2C12 myoblasts, resulted in: 1) abrogation of terminal differentiation-as evidenced by a marked decrease in the myoblast fusion index and a significant reduction of Myogenin, MyoD, Sirtuin 1 and Troponin T protein expression-restored upon MyoD overexpression; 2) a decrease in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and citrate synthase protein expression reflecting an alteration of mitochondrial density; and 3) an increased production of reactive oxygen species (ROS) mirrored by the decreased activity of manganese superoxide dismutase (MnSOD). Altogether our data demonstrate that SIRT3 mainly regulates myoblast differentiation via its influence on mitochondrial activity.

Communications biology, Feb 12, 2021

Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5-13% of individua... more Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5-13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

Journal of Molecular and Cellular Cardiology, Aug 1, 2016

Highlights-Early postnatal cardiac mTOR inactivation rapidly leads to dilated cardiomyopathy (DCM... more Highlights-Early postnatal cardiac mTOR inactivation rapidly leads to dilated cardiomyopathy (DCM) and heart failure.-mTOR regulates cardiomyocyte growth by controlling translational efficiency through 4E-BP1-dependent and-independent mechanisms.-mTOR depletion leads to cardiomyocyte apoptosis associated with hypoxia and biomechanical stress and involving JNK/p53 pro-apoptotic pathways.-Infant mTOR-depleted cardiomyocyte apoptosis is not associated to activation of the pro-apoptotic MST1/Hippo pathway in contrast to Rictor Knockout hearts.

Experimental Cell Research, Aug 1, 2000

Proliferating myoblasts already express MyoD before the induction of differentiation. Overexpress... more Proliferating myoblasts already express MyoD before the induction of differentiation. Overexpression of MyoD in normal and transformed cell lines was shown to block cells from entering S phase, suggesting that the MyoD growth suppressive effect must be tightly controlled in growing myoblasts. Here we show that during G1 phase, but not in G2, MyoD abundance is down-regulated by the ubiquitin-proteasome pathway through phosphorylation of serine 200. Roscovitine, a specific inhibitor of cyclin-Cdk2 complexes, prevents both phosphorylation and degradation of MyoD in G1. Inhibition of the ubiquitin-dependent proteasome pathway by MG132 results in stabilization of MyoD-wt, with little effect on a MyoD mutant where serine 200 is replaced by an alanine. Our results show that MyoD Ser200 is the substrate for phosphorylation by cyclin E-Cdk2 stimulating its degradation by the ubiquitin-proteasome system which controls MyoD levels in G1. Phosphorylation/ degradation of MyoD at the end of G1 thus represents the regulatory checkpoint in growing myoblasts allowing progression into S phase in a manner similar to the recently examplified cdk2-phosphorylation/degradation of p27 Kip1 .

Nature Communications, Apr 27, 2022

Nature Communications, Apr 19, 2022

Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie re... more Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making "CR mimetics" of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

Cell Metabolism, May 1, 2013

Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a ... more Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.

Scientific Reports, Aug 22, 2019

thyroid hormone is a major regulator of skeletal muscle development and repair, and also a key re... more thyroid hormone is a major regulator of skeletal muscle development and repair, and also a key regulator of mitochondrial activity. We have previously identified a 43 kDa truncated form of the nuclear T3 receptor TRα1 (p43) which stimulates mitochondrial activity and regulates skeletal muscle features. However, its role in skeletal muscle regeneration remains to be addressed. To this end, we performed acute muscle injury induced by cardiotoxin in mouse tibialis in two mouse models where p43 is overexpressed in or depleted from skeletal muscle. The measurement of muscle fiber size distribution at different time point (up to 70 days) upon injury lead us to unravel requirement of the p43 signaling pathway for satellite cells dependent muscle regeneration; strongly delayed in the absence of p43; whereas the overexpression of the receptor enhances of the regeneration process. In addition, we found that satellite cells derived from p43-Tg mice display higher proliferation rates when cultured in vitro when compared to control myoblasts, whereas p43−/− satellites shows reduced proliferation capacity. These finding strongly support that p43 plays an important role in vivo by controling the duration of skeletal muscle regeneration after acute injury, possibly through the regulation of mitochondrial activity and myoblasts proliferation.

Skeletal Muscle, Mar 21, 2016

Background: The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network o... more Background: The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism. Results: We characterized the metabolic phenotype of young and old raptor muscle knockout (RAmKO) and TSC1 muscle knockout (TSCmKO) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated, respectively. Ten-week-old RAmKO mice are lean and insulin resistant with increased energy expenditure, and they are resistant to a high-fat diet (HFD). This correlates with an increased expression of histone deacetylases (HDACs) and a downregulation of genes involved in glucose and fatty acid metabolism. Ten-week-old TSCmKO mice are also lean, glucose intolerant with a decreased activation of protein kinase B (Akt/PKB) targets that regulate glucose transporters in the muscle. The mice are resistant to a HFD and show reduced accumulation of glycogen and lipids in the liver. Both mouse models suffer from a myopathy with age, with reduced fat and lean mass, and both RAmKO and TSCmKO mice develop insulin resistance and increased intramyocellular lipid content. Conclusions: Our study shows that alterations of mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism. While both inhibition and constitutive activation of mTORC1 induce leanness and resistance to obesity, changes in the metabolism of muscle and peripheral organs are distinct. These results indicate that a balanced mTORC1 signaling in the muscle is required for proper metabolic homeostasis.

Science Signaling, Nov 10, 2015

Skeletal muscle is the largest organ, comprising 40% of the total body lean mass, and affects who... more Skeletal muscle is the largest organ, comprising 40% of the total body lean mass, and affects whole-body metabolism in multiple ways. We investigated the signaling pathways involved in this process using TSCmKO mice, which have a skeletal muscle-specific depletion of TSC1 (tuberous sclerosis complex 1). This deficiency results in the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1), which enhances cell growth by promoting protein synthesis. TSCmKO mice were lean, with increased insulin sensitivity, as well as changes in white and brown adipose tissue and liver indicative of increased fatty acid oxidation. These differences were due to increased plasma concentrations of fibroblast growth factor 21 (FGF21), a hormone that stimulates glucose uptake and fatty acid oxidation. The skeletal muscle of TSCmKO mice released FGF21 because of mTORC1-triggered endoplasmic reticulum (ER) stress and activation of a pathway involving PERK (protein kinase RNA-like ER kinase), eIF2α (eukaryotic translation initiation factor 2α), and ATF4 (activating transcription factor 4). Treatment of TSCmKO mice with a chemical chaperone that alleviates ER stress reduced FGF21 production in muscle and increased body weight. Moreover, injection of function-blocking antibodies directed against FGF21 largely normalized the metabolic phenotype of the mice. Thus, sustained activation of mTORC1 signaling in skeletal muscle regulated whole-body metabolism through the induction of FGF21, which, over the long term, caused severe lipodystrophy.

Physiological Reviews, Jul 1, 2015

The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibe... more The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia. I. INTRODUCTION 809 II. PHYSIOLOGY OF NEUROMUSCULAR... 810 III. DEVELOPMENT OF THE RODENT... 811 IV. MOLECULES IMPORTANT FOR NMJ... 815 V. REGULATION OF SYNAPTIC AChR... 823 VI. MECHANISMS OF MUSCLE WASTING 827 VII. LOSS OF MUSCLE MASS IN AGING...

Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from ... more Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated...

Cancer research, Mar 22, 2024

Research Square (Research Square), Feb 12, 2020

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Oct 23, 2012

PLOS ONE, Dec 9, 2014

HAL (Le Centre pour la Communication Scientifique Directe), Sep 26, 2012

Research Square (Research Square), Jul 15, 2020

Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-t... more Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-term disability and higher mortality. Bolus nutrition (30-60 min period), while having a similar incidence of aspiration as continuous feeding, seems to provide metabolic bene ts through increased muscle protein synthesis due to higher leucine peaks. To date, clinical evidence on achievement of nutritional goals and in uence of bolus nutrition on skeletal muscle metabolism in ICU patients is lacking. The aim of the Pro BoNo study (Protein Bolus Nutrition) is to compare intermittent and continuous enteral feeding with a speci c highprotein formula. We hypothesise that target quantity of protein is reached earlier (within 36 hours) by an intermittent feeding protocol with a favourable in uence on muscle protein synthesis. Methods Pro BoNo is a prospective randomised controlled study aiming to compare the impact of intermittent and continuous enteral feeding on preventing muscle wasting in 60 critically ill patients recruited during the rst 48 hours after ICU admission. The primary outcome measure is the time until the daily protein target (≥1.5 g protein/kg bodyweight/24h) is achieved. Secondary outcome measures include tolerance of enteral feeding and evolution of glucose, urea and IGF-1. Ultrasound and muscle biopsy of the quadriceps will be performed. Discussion The Basel Pro BoNo study aims to collect innovative data on the effect of intermittent enteral feeding of critically ill patients on muscle wasting.

BMC Biology, Jul 3, 2020

PLOS ONE, Dec 9, 2014

Communications biology, Feb 12, 2021

Journal of Molecular and Cellular Cardiology, Aug 1, 2016

Experimental Cell Research, Aug 1, 2000

Nature Communications, Apr 27, 2022

Nature Communications, Apr 19, 2022

Cell Metabolism, May 1, 2013

Scientific Reports, Aug 22, 2019

Skeletal Muscle, Mar 21, 2016

Science Signaling, Nov 10, 2015

Physiological Reviews, Jul 1, 2015