FGF21 as Modulator of Metabolism in Health and Disease

Fibroblast growth factor 21 (FGF21) is a hormone that regulates important metabolic pathways. FGF21 is expressed in several metabolically active organs and interacts with different tissues. The FGF21 function is complicated and well debated due to its different sites of production and actions. Striated muscles are plastic tissues that undergo adaptive changes within their structural and functional properties in order to meet their different stresses, recently, they have been found to be an important source of FGF21. The FGF21 expression and secretion from skeletal muscles happen in both mouse and in humans during their different physiological and pathological conditions, including exercise and mitochondrial dysfunction. In this review, we will discuss the recent findings that identify FG21 as beneficial and/or detrimental cytokine interacting as an autocrine or endocrine in order to modulate cellular function, metabolism, and senescence

Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence

Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging

Transcription Factor EB Controls Metabolic Flexibility during Exercise

The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism

Biology of Lysiphlebus fabarum following cold storage of larvae and pupae

Citation: Mahi, H., Rasekh, A., Michaud, J. P., & Shishehbor, P. (2014). The biology of Lysiphlebus fabarum (Braconidae, Aphidiinae) following cold storage of larvae and pupae. Retrieved from http://krex.ksu.eduCold storage is a one means of preserving parasitoids prior to release in augmentation biological control programs. This study examined the feasibility of storing larval and pupal stages of a sexual population of Lysiphlebus fabarum Marshall (Braconidae: Aphidiinae) at 6.0 and 8.0 °C (± 1.0 °C), 50–60% RH, and 14L:10D photoperiod. These life stages were stored for periods of 1, 2 and 3 weeks under fluctuating thermal regimes (2.0 h daily at 21.0 ± 1.0 °C). Generally, pupae gave better results than larvae, 6.0 °C was better than 8.0 °C, and were better than constant, considering wasp survival, wasp size (tibial and antennal lengths), egg load and egg size. The best results were obtained with pupae stored for two weeks under a fluctuating temperature regime at 6.0 °C. Females emerging from this treatment did not differ from controls (developing directly at 21.0 °C) in body size, egg size, or progeny sex ratio and suffered less than 20% mortality. Egg loads were reduced in these wasps, but the reductions were substantially less than occurred in other two week storage treatments. Wasps stored in this manner successfully parasitized similar numbers of aphids as controls and produced similar progeny sex ratios. These results reveal a suitable set of low temperature conditions that can be used to delay the development of L. fabarum for two weeks with minimal impacts on wasp fitness

defective mitochondrial trna taurine modification activates global proteostress and leads to mitochondrial disease

Summary: A subset of mitochondrial tRNAs (mt-tRNAs) contains taurine-derived modifications at 34U of the anticodon. Loss of taurine modification has been linked to the development of mitochondrial diseases, but the molecular mechanism is still unclear. Here, we showed that taurine modification is catalyzed by mitochondrial optimization 1 (Mto1) in mammals. Mto1 deficiency severely impaired mitochondrial translation and respiratory activity. Moreover, Mto1-deficient cells exhibited abnormal mitochondrial morphology owing to aberrant trafficking of nuclear DNA-encoded mitochondrial proteins, including Opa1. The mistargeted proteins were aggregated and misfolded in the cytoplasm, which induced cytotoxic unfolded protein response. Importantly, application of chemical chaperones successfully suppressed cytotoxicity by reducing protein misfolding and increasing functional mitochondrial proteins in Mto1-deficient cells and mice. Thus, our results demonstrate the essential role of taurine modification in mitochondrial translation and reveal an intrinsic protein homeostasis network between the mitochondria and cytosol, which has therapeutic potential for mitochondrial diseases. : Taurine modification of mitochondrial tRNA is associated with mitochondrial disease. Fakruddin et al. find that taurine modification is indispensable for mitochondrial protein translation. The authors also find that deficiency of taurine modification impairs a mitochondrial-cytosolic proteostatic network through an Opa1-dependent mechanism and demonstrate the therapeutic potential of chemical chaperones. Keywords: tRNA, modification, taurine, mitochondria, Opa

Tuning the magnetic properties of NiPS3through organic-ion intercalation

Atomically thin van der Waals magnetic crystals are characterized by tunable magnetic properties related to their low dimensionality. While electrostatic gating has been used to tailor their magnetic response, chemical approaches like intercalation remain largely unexplored. Here, we demonstrate the manipulation of the magnetism in the van der Waals antiferromagnet NiPS3 through the intercalation of different organic cations, inserted using an engineered two-step process. First, the electrochemical intercalation of tetrabutylammonium cations (TBA+) results in a ferrimagnetic hybrid compound displaying a transition temperature of 78 K, and characterized by a hysteretic behavior with finite remanence and coercivity. Then, TBA+ cations are replaced by cobaltocenium via an ion-exchange process, yielding a ferrimagnetic phase with higher transition temperature (98 K) and higher remanent magnetization. Importantly, we demonstrate that the intercalation and cation exchange processes can be carried out in bulk crystals and few-layer flakes, opening the way to the integration of intercalated magnetic materials in devices.The authors acknowledge R. Llopis and A. Eleta for technical support. This work is supported by “la Caixa” Foundation (ID 100010434), under the agreement LCF/BQ/PI19/11690017, by the Spanish MICINN under Project PID2019-108153GA-I00, RTI2018-094861-B-100 and under the María de Maeztu Units of Excellence Program (MDM-2016-0618). B. M.-G. thanks Gipuzkoa Council (Spain) in the frame of Gipuzkoa Fellows Program.Peer reviewe

OPA1 orchestrates precocious senescence, degeneration of multiple organs and premature death thought inflammation and metabolic changes

A healthy mitochondrial network is essential for post-mitotic tissues like muscles. During aging sarcopenia, mitochondria-shaping machinery declines. On the contrary, lifelong exercise preserves it. OPA1 is a profusion protein that plays an essential role in mitochondrial dynamics. Interesting, OPA1 protein decreases in sedentary seniors and in 18 months-old mice. Exercise in aged mice is sufficient to increase OPA1 levels in old muscles. To address the OPA1 role in skeletal muscle and further investigate its involvement in aging, we generated muscle-specific ko mice. Indeed, Opa1 mice show severe precocious senescence, degeneration of multiple organs, and premature death. Surprisingly, mitochondrial dysfunction in muscle tissue is sufficient to directly drive metabolic changes and systemic inflammation by increasing the expression and secretion of the mitokine FGF21. Although the simultaneous deletion of OPA1 and FGF21 almost reverted the phenotype, we have new evidence that connects aging with mitochondrial dysfunction, autophagy alteration, and inflammation. Our findings underscore the central role of muscle mitochondria in the regulation of signaling pathways and the maintenance of total body metabolism, underlying the importance of a functional mitochondrial population for healthy aging.Un network funzionale di mitocondri e essenziale per un tessuto post-mitotico come il muscolo. Il macchinario delle dinamiche mitocondriali e downregolato nella sarcopenia e preservato nei soggetti che fanno attvita fisica costante. La proteina OPA1, coinvolta nel processo di fusione mitocondriale, gioca un ruolo essenziale nelle dinamiche mitocondriali. I livelli di espressione di questa proteina correlano significativamente con la disfunzione muscolare associata all’invecchiamento, in umani e topi. Per caratterizzare il ruolo della proteina OPA1 nel muscolo scheletrico, e soprattutto il suo coinvolgimento nell’invecchiamento, abbiamo generato 2 modelli di delezione del gene nel tessuto muscolare. Il primo modello (costitutivo) presenta la delezione del gene a partire dallo stadio embrionale e il secondo (condizionale) permette di effettuare la delezione in seguito a somministrazione farmacologica, in eta adulta. Il modello costitutivo ha un fenotipo molto grave che porta alla morte dopo otto giorni post-nascita. Per questa ragione ci siamo concentati su quello condizionale. I topi adulti con delezione di OPA1 mostrano un fenotipo di invecchiamento precoce. Il blocco della fusione e sufficiente a indurre cambiamenti metabolici e infiammazione sistemica. Il fattore chiave in questo processo e la miochina FGF21. La delezione simultanea di OPA1 e FGF21 non presenta le principali caratteristiche patologiche del fenotipo, ma pensiamo che altri fattori siano coinvolti nel processo di invecchiamento precoce. Dal confronto tra i diversi modelli a nostra disposizione (Opa1 ko, Opa1/fgf21 ko, Drp1 ko e Opa1/Drp1 ko), che a differenza degli OPA1 ko non muoiono ma hanno livello di FGF21 elevati, abbiamo capito che la differenza principale e l’infiammazione sistemica, presente solo negli Opa1 ko. In particolare, l’unica citochina di origine muscolare espressa per un periodo prolungato e secreta e l’interleuchina 6 (IL6). Vista la mancanza di dati in letteratura sui segnali molecolari che portano all’induzione di IL6, nel muscolo scheletrico, ci siamo concentrati su questo aspetto

Recovering Occlusion Aware Depth and Image using Rotating Point Spread Function.

embargoed_20240709La stima della profondità rappresenta una sfida in qualsiasi am- bito relativo alle applicazioni di Computer Vision. In particolare, se si considerano le limitazioni delle tecniche tradizionali in fotografia. Nel campo della stima della profondità monoculare, la presenza degli oc- clusion boundaries è uno dei problemi più critici; essi possono essere individuati come discontinuità di profondità lungo i bordi degli oggetti, dove l’oggetto in primo piano copre gli oggetti sullo sfondo. Ciò comporta una stima della profondità incompleta o inaccurata, rendendo difficile es- trarre informazioni significative dalle scene in esame. A tal fine, recenti studi hanno dimostrato come i metodi basati sulla coded aperture, uti- lizzando maschere di fase e/o di ampiezza, possano codificare segnali di profondità all’interno di immagini 2D utilizzando le Point Spread Func- tions (PSF) dipendenti dalla profondità. In questa tesi, proponiamo un nuovo approccio per affrontare il problema degli occlusion boundaries con l’obiettivo di migliorare il risultato finale per la stima della profon- dità. Nel nostro caso, la dipendenza dalla profondità è introdotta da una maschera di fase che viene ottimizzata assieme ai pesi di una rete neurale con approccio end-to-end. In fase di sviluppo viene utilizzato un mod- ello di camera che permette di simulare l’intero sistema presente in una fotocamera reale che può stimare affidabilmente la mappa di profondità a partire da una singola immagine RGB. Rispetto ai metodi più comuni utilizzati per risolvere i problemi degli occlusion boundaries nell’ambito della monocular depth estimation, la nostra pipeline finale utilizza uno step di pre-condizionamento, inserito con lo scopo di ridurre lo sforzo totale richiesto dalla rete, riducendo così il tempo totale necessario per addestrare la rete e ottenendo risultati migliori in termini di accuratezza sulla stima finale. In questo step di precondizionamento viene calco- lata una stima rozza della profondità, modificando un noto algoritmo di riduzione del rumore che ricostruisce i dettagli dell’imagine nelle regioni che corrispondo a specifici livelli di profondità. In questo modo otteni- amo una imagine stratificata e la rete neurale finale dovrà eseguire solo una associazione tra i vari livelli. Inoltre, per affrontare il problema della degradazione nella qualità dell’immagine dovuta agli effetti di sfocatura PSF, la nostra rete può recuperare l’immagine completamente a fuoco insieme alla stima di pro- fondità, a partire dal risultato dello step di pre-condizionamento.Depth estimation is a key challenge in Computer Vision. In partic- ular, when we consider the limitations of traditional techniques. In the monocular depth estimation field, the presence of occlusion boundaries is one of the most critical issues, we can find them as depth discontinu- ity along the edges of the objects, where the object in the foreground occludes the objects in the background. This results in incomplete or inaccurate depth prediction, making it difficult to extract accurarte ge- ometry information from the scene. To this end, recent studies have shown how coded aperture-based methods using phase and/or amplitude masks can encode strong depth cues within 2D images using depth-dependent point spread functions (PSFs). In this thesis, we propose a new approach to address the prob- lem of occlusion boundaries with the aim of improving the result for depth estimation. In our case, the depth dependency is achieved using a phase mask that is jointly optimized with the weights of a convolutional neural network in an end-to-end manner. A fully-working camera model is used to simulate the imaging system that can reliably estimate the depth map starting from a single RGB image. Compared to the most common methods used to solve occlusion boundaries in monocular depth estimation problems, in our final pipeline we propose a preconditioning step that aims at reducing the total effort required from the neural net- work, reducing the total time required to train the network, and achiev- ing better results in terms of accuracy over the final estimate. In this preconditioning step is already computed a raw estimate of the depth, using a well-known deblurring strategy that reconstruct the details of the image in the region that correspond to a specific level of depth. In this way a layered image is already processed and the final neural network performed only an association operation between the various layers. Moreover, to address the problem of image quality degradation due to the PSF-Blurring effects, our network can recover the all-in-sharp image along with the depth estimate, starting from the output of the preconditioning step