Homeostatic Signals Research Articles

Hepatic vagal afferents convey clock-dependent signals to regulate circadian food intake

Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.

Accumbal serotonin hypofunction and dopamine hyperfunction due to chronic stress and palatable food intake in rats

ABSTRACT Feeding is regulated by energy homeostatic and pleasure-induced rewarding signals. Palatable food intake modifies serotonergic (5-HT) and dopaminergic (DA) pathways in nucleus accumbens, inducing neuronal maladaptations that favor hyperphagia for high-energy dense food and consequent obesity. Chronic stress is an environmental condition that increases the preference for palatable food by modulating brain DA and 5-HT metabolism. Objective: To evaluate the association between changes in accumbal 5-HT and DA metabolism and the effects of chronic stress, palatable food intake and their interaction with satiety/hunger condition. Methods: Wistar rats were housed in pairs (non-stressed) or individually (stressed), fed with chow or chocolate milk plus chow (Ch) for 2 weeks (4 groups); then 6 animals/group were 48 h fasted or maintained ad libitum; the rest were fasted and re-fed for 2 h either with chow or Ch. Results: Rats with prolonged high-energy density food intake and re-fed with chow showed reduced 5-HT metabolism, although there was no association with animals’ feeding behavior. In contrast, after re-fed with palatable food, stressed chow-fed rats had increased 5-HT turnover, which decreased in Ch re-fed rats, supporting that palatable food might induce positive mood changes related to high extracellular 5-HT in limbic regions. Discussion: Rats with prolonged palatable food intake exhibited high accumbal DA turnover independently of stress exposure, supporting its relation with the development of high-energy dense food hyperphagia. As accumbal 5-HT and DA metabolism changed due to fasting or re-feeding, alterations could represent the interaction of energy homeostatic and hedonic feeding signaling in animals.

Homeostatic signals, including IL-7 and self-MHC recognition, induce the development of peripheral helper T cells, which are enriched in the joints of rheumatoid arthritis

Homeostatic signals, including IL-7 and self-MHC recognition, induce the development of peripheral helper T cells, which are enriched in the joints of rheumatoid arthritis

Increased Frequency of Circulating Activated FOXP3+ Regulatory T Cell Subset in Patients with Chronic Lymphocytic Leukemia Is Associated with the Estimate of the Size of the Tumor Mass, STAT5 Signaling and Disease Course during Follow-Up of Patients on Therapy.

Advanced chronic lymphocytic leukemia (CLL) is accompanied by increased circulating regulatory T cells (Tregs) and increased susceptibility to severe infections, which were also shown to entail a striking induction of FOXP3 expression in Tregs. As homeostasis of the most suppressive CD45RA-FOXP3high activated Treg (aTreg) subset differs, it is critical to analyse homeostatic signalling in Treg subsets. In this study, by using conventional and imaging flow cytometry, we monitored STAT5 signalling/phosphorylation (pSTAT5) and investigated Treg subsets in relation to the Binet stage, the total tumor mass score (TTM) and the disease course during a follow-up of 37 patients with CLL. The aTreg percentage was significantly increased among CD4+ T cells from patients with advanced disease and significantly correlated with the TTM. A subgroup of patients with higher aTreg percentages among CD4+FOXP3+ T cells at the start of therapy was characterised by more frequent episodes of severe infections during follow-up. The results suggesting that an aTreg fraction could represent a possible marker of a severe disease course with infectious complications. Augmented homeostatic STAT5 signalling could support aTreg expansion, as higher pSTAT5 levels were significantly correlated with an increased aTreg frequency among CD4+FOXP3+ T cells during the follow-up of patients on therapy, as well as following SARS-CoV-2 antigen-specific stimulation in vitro.

Interplay of Dopamine and Food Signals: Examining the Interaction of Dopamine and Homeostatic Signals in Food-motivated Behavior

Interplay of Dopamine and Food Signals: Examining the Interaction of Dopamine and Homeostatic Signals in Food-motivated Behavior

A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss

In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.

The nucleus accumbens shell: a neural hub at the interface of homeostatic and hedonic feeding.

Feeding behavior is a complex physiological process regulated by the interplay between homeostatic and hedonic feeding circuits. Among the neural structures involved, the nucleus accumbens (NAc) has emerged as a pivotal region at the interface of these two circuits. The NAc comprises distinct subregions and in this review, we focus mainly on the NAc shell (NAcSh). Homeostatic feeding circuits, primarily found in the hypothalamus, ensure the organism's balance in energy and nutrient requirements. These circuits monitor peripheral signals, such as insulin, leptin, and ghrelin, and modulate satiety and hunger states. The NAcSh receives input from these homeostatic circuits, integrating information regarding the organism's metabolic needs. Conversely, so-called hedonic feeding circuits involve all other non-hunger and -satiety processes, i.e., the sensory information, associative learning, reward, motivation and pleasure associated with food consumption. The NAcSh is interconnected with hedonics-related structures like the ventral tegmental area and prefrontal cortex and plays a key role in encoding hedonic information related to palatable food seeking or consumption. In sum, the NAcSh acts as a crucial hub in feeding behavior, integrating signals from both homeostatic and hedonic circuits, to facilitate behavioral output via its downstream projections. Moreover, the NAcSh's involvement extends beyond simple integration, as it directly impacts actions related to food consumption. In this review, we first focus on delineating the inputs targeting the NAcSh; we then present NAcSh output projections to downstream structures. Finally we discuss how the NAcSh regulates feeding behavior and can be seen as a neural hub integrating homeostatic and hedonic feeding signals, via a functionally diverse set of projection neuron subpopulations.

Trauma promotes heparan sulfate modifications and cleavage that disrupt homeostatic gene expression in microvascular endothelial cells.

Introduction: Heparan sulfate (HS) in the vascular endothelial glycocalyx (eGC) is a critical regulator of blood vessel homeostasis. Trauma results in HS shedding from the eGC, but the impact of trauma on HS structural modifications that could influence mechanisms of vascular injury and repair has not been evaluated. Moreover, the effect of eGC HS shedding on endothelial cell (EC) homeostasis has not been fully elucidated. The objectives of this work were to characterize the impact of trauma on HS sulfation and determine the effect of eGC HS shedding on the transcriptional landscape of vascular ECs. Methods: Plasma was collected from 25 controls and 49 adults admitted to a level 1 trauma center at arrival and 24h after hospitalization. Total levels of HS and angiopoietin-2, a marker of pathologic EC activation, were measured at each time point. Enzymatic activity of heparanase, the enzyme responsible for HS shedding, was determined in plasma from hospital arrival. Liquid chromatography-tandem mass spectrometry was used to characterize HS di-/tetrasaccharides in plasma. In vitro work was performed using flow conditioned primary human lung microvascular ECs treated with vehicle or heparinase III to simulate human heparanase activity. Bulk RNA sequencing was performed to determine differentially expressed gene-enriched pathways following heparinase III treatment. Results: We found that heparanase activity was increased in trauma plasma relative to controls, and HS levels at arrival were elevated in a manner proportional to injury severity. Di-/tetrasaccharide analysis revealed lower levels of 3-O-sulfated tetramers with a concomitant increase in ΔIIIS and ΔIIS disaccharides following trauma. Admission levels of total HS and specific HS sulfation motifs correlated with 24-h angiopoietin-2 levels, suggesting an association between HS shedding and persistent, pathological EC activation. In vitro pathway analysis demonstrated downregulation of genes that support cell junction integrity, EC polarity, and EC senescence while upregulating genes that promote cell differentiation and proliferation following HS shedding. Discussion: Taken together, our findings suggest that HS cleavage associated with eGC injury may disrupt homeostatic EC signaling and influence biosynthetic mechanisms governing eGC repair. These results require validation in larger, multicenter trauma populations coupled with in vivo EC-targeted transcriptomic and proteomic analyses.

Regulation of bone homeostasis: signaling pathways and therapeutic targets.

As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.

Trioxidized cysteine and aging: a molecular binomial that extends far beyond classical proteinopathic paradigms.

Increased oxidative stress (OS) and the disruption of the equilibrium between the production of reactive oxygen species and antioxidants are key molecular features of unhealthy aging. OS results in the formation of oxidative posttranslational modifications (PTMs), some of which involve cysteine (Cys) residues in aging proteomes, and specifically, the formation of trioxidized Cys (t-Cys), which leads to permanent protein damage. Recent findings in rodents have uncovered that irregular regulation of t-Cys residues in the aging proteome disrupts homeostatic phosphorylation signaling, resulting in alterations to proteins that are analogous to those caused by phosphorylated serine (p-Ser) residues. This work contextualizes these significant findings and discusses the implications and molecular role(s) of t-Cys in the aging proteome. Furthermore, we present novel data, validating the increase of specific t-Cys sites associated with aging in a blood-related circulating human proteome. The scope and findings included here support the hypothesis that t-Cys residues may serve as important mechanistic and biological markers, warranting further exploration in the context of unhealthy aging and age-related major diseases.

Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.

Homeostatic Signal Convergence in Vagal Baroreceptors.

Homeostatic Signal Convergence in Vagal Baroreceptors.

Chemogenetic activation of arcuate nucleus NPY and NPY/AgRP neurons increases feeding behaviour in mice

Neuropeptide Y (NPY) plays a crucial role in controlling energy homeostasis and feeding behaviour. The role of NPY neurons located in the arcuate nucleus of the hypothalamus (Arc) in responding to homeostatic signals has been the focus of much investigation, but most studies have used AgRP promoter-driven models, which do not fully encompass Arc NPY neurons. To directly investigate NPY-expressing versus AgRP-expressing Arc neurons function, we utilised chemogenetic techniques in NPY-Cre and AgRP-Cre animals to activate Arc NPY or AgRP neurons in the presence of food and food-related stimuli. Our findings suggest that chemogenetic activation of the broader population of Arc NPY neurons, including AgRP-positive and AgRP-negative NPY neurons, has equivalent effects on feeding behaviour as activation of Arc AgRP neurons. Our results demonstrate that these Arc NPY neurons respond specifically to caloric signals and do not respond to non-caloric signals, in line with what has been observed in AgRP neurons. Activating Arc NPY neurons significantly increases food consumption and influences macronutrient selection to prefer fat intake.

YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes.

Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease - affecting >1:500 individuals. Advanced forms of HCM clinically present with hypercontractility, hypertrophy and fibrosis. Several single-point mutations in b-myosin heavy chain (MYH7) have been associated with HCM and increased contractility at the organ level. Different MYH7 mutations have resulted in increased, decreased, or unchanged force production at the molecular level. Yet, how these molecular kinetics link to cell and tissue pathogenesis remains unclear. The Hippo Pathway, specifically its effector molecule YAP, has been demonstrated to be reactivated in pathological hypertrophic growth. We hypothesized that changes in force production (intrinsically or extrinsically) directly alter the homeostatic mechano-signaling of the Hippo pathway through changes in stresses on the nucleus. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we asked whether homeostatic mechanical signaling through the canonical growth regulator, YAP, is altered 1) by changes in the biomechanics of HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We use genetically edited hiPSC-CM with point mutations in MYH7 associated with HCM, and their matched controls, combined with micropatterned traction force microscopy substrates to confirm the hypercontractile phenotype in MYH7 mutants. We next modulate contractility in healthy and disease hiPSC-CMs by treatment with positive and negative inotropic drugs and demonstrate a correlative relationship between contractility and YAP activity. We further demonstrate the activation of YAP in both HCM mutants and healthy hiPSC-CMs treated with contractility modulators is through enhanced nuclear deformation. We conclude that the overactivation of YAP, possibly initiated and driven by hypercontractility, correlates with excessive CCN2 secretion (connective tissue growth factor), enhancing cardiac fibroblast/myofibroblast transition and production of known hypertrophic signaling molecule TGFβ. Our study suggests YAP being an indirect player in the initiation of hypertrophic growth and fibrosis in HCM. Our results provide new insights into HCM progression and bring forth a testbed for therapeutic options in treating HCM.

Modulation of WNT signalling by inflammatory factor TWEAK, and its consequences on fibroblast-epithelial communication

BACKGROUND AND AIMS: A single layer of epithelial cells that are supported by resident mucosal fibroblasts, provides an intestinal barrier against pathogens. In Inflammatory Bowel Disease (IBD), this barrier is disrupted by mechanisms which are poorly understood. Intestinal fibroblasts produce WNT, BMP and Notch mediators that contribute to epithelial homeostasis and an impairment on these signals results in the loss of barrier integrity which has been observed in IBD. In fact, fibroblasts producing these signals may be lost during inflammation. Yet the mediators and mechanism that drive this loss of homeostatic stromal-derived signals are unknown. TWEAK is a member of the tumour necrosis factor superfamily (TNFSF) that was found to be upregulated in IBD biopsies and dysregulated tissue repair and promote chronic inflammation in in vivo murine models. However, whether TWEAK exerts its effects on fibroblasts and how these may contribute to barrier breakdown remains unknown. My central hypothesis is that TWEAK dysregulates the crosstalk between fibroblasts and epithelial cells in the intestinal tract by impairing a homeostatic signalling network. METHODS: To assess the effect of TWEAK on WNT signalling and wound healing in fibroblasts and epithelial cells, the expression of WNT ligands and receptors were assessed. Primary human colonic fibroblasts and human colonic epithelial cells were stimulated with TWEAK at various time points and analysed by qPCR, Western blot and Flow cytometry and scratch wound assay. RESULTS: Both Fibroblasts and epithelial cells displayed abundant Fn14 surface receptor, although epithelial cells at a level lower than that found on colonic fibroblasts. Transcriptional signatures at gene RSPO2 (0.5-fold ± decrease, *p<0.05, n=4), WNT5A (1 fold ± decrease, **p<0.01, n=4) and BMP6 (1 fold ± decrease, ***p<0.001, n=4) and protein level RSPO2 (50% ± decrease respectively, n=5) showed a TWEAK-mediated suppression after prolonged exposure (24-48h), but not in epithelial cells. Moreover, TWEAK delayed fibroblast healing capacity after 24h (50% ± decrease in wound closure, n=4) in a wound-scratch assay. CONCLUSION: TWEAK represses the expression of homeostatic factors in colonic fibroblasts but not on epithelial cells, suggesting this mechanism could be specific to the intestinal stroma. The effect that this impairment of WNT signals in stromal cells may have on their differentiation and communication with the epithelium will be subject for further study. UCD Ad Astra PhD Scholarship. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Contribution Of TRPV4 Channels To Calcium Signaling Profiles Of The Lung Microvascular Endothelium Under Acidic pH

Maintenance of lung endothelial barrier integrity is achieved to a great extent through effcient homeostatic endothelial calcium signaling in the lung microvasculature. The transient receptor potential vanilloid 4 (TRPV4), a non-selective calcium permeable channel has been implicated in several pulmonary pathologies involving lung barrier disruption. These channels are activated by various physical forces and chemical stimuli, but their underlying contribution to inherent and distinct microvascular endothelial Ca2+ signaling profiles are unknown. We previously assessed the role of TRPV4 channels in basal Ca2+ signaling dynamics of the pulmonary microcirculation under differing conditions of stretch and temperature. In the current study, we evaluate the impact of acidic pH (7.1, resembling acidosis) on the distinct endothelial Ca2+ signaling events in the mouse lung microcirculation and examine the participation of TRPV4 channels. Lung slices isolated from the Cdh5-GCaMP8 mice (transgenic mice with Ca2+-dependent fluorescent indicator expressed specifically within vascular endothelial cells) were mounted on Sylgard inserts with HEPES buffer (pH 7.45) and imaged for their basal signaling events using spinning disk confocal microscopy. After an initial baseline recording, the bathing solution was replaced with acidic HEPES buffer (pH 7.1) and recordings were made for approximately two minutes at 5 frames per second. These slices were then treated with the TRPV4 channel inhibitor GSK2193874 (3μM) or vehicle. The recorded image sequences were analyzed by using ImageJ and our custom signal tracking software S8, for quantification of the Ca2+ signaling profiles through event frequency, amplitude, duration and spread. Subjecting the lung slices to pH 7.1 increased the amplitude and spatial spread of the signaling events but the duration and frequency of the events remained relatively constant when compared to baseline recorded events. Addition of the channel blocker diminished the signaling event frequency, amplitude and spatial spread of the lung tissues. The normal pH and vehicle control for the above experiments did not show any relative change from the baseline signaling event profiles. To summarize, treating the lung slices to acidic pH increased the event amplitude and event spatial area distributions, indicating widespread activation of Ca2+ entry events. These increased event parameters were reduced upon addition of the antagonist, suggesting higher contribution of TRPV4 channel induced Ca2+ signaling events under acidic pH. We conclude that the channels contribute minimally to basal dynamics under homeostatic conditions but are activated to a greater extent under stimulations resembling pathological conditions like acidosis or acid aspirations. NIH P01 HL066299, R01 HL155288, NIH S10 0D020149. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses

The transition of naive T lymphocytes into antigenically activated effector cells is associated with a metabolic shift from oxidative phosphorylation to aerobic glycolysis. This shift facilitates production of the key anti-tumor cytokine interferon (IFN)-γ; however, an associated loss of mitochondrial efficiency in effector Tcells ultimately limits anti-tumor immunity. Memory phenotype (MP) Tcells are a newly recognized subset that arises through homeostatic activation signals following hematopoietic transplantation. We show here that human CD4+ MP cell differentiation is associated with increased glycolytic and oxidative metabolic activity, but MP cells retain less compromised mitochondria compared to effector CD4+ Tcells, and their IFN-γ response is less dependent on glucose and more reliant on glutamine. MP cells also produced IFN-γ more efficiently in response to weak Tcell receptor (TCR) agonism than effectors and mediated stronger responses to transformed B cells. MP cells may thus be particularly well suited to carry out sustained immunosurveillance against neoplastic cells.

Xanthurenic acid: A role in brain intercellular signaling.

Xanthurenic acid (XA) raises a growing multidisciplinary interest based upon its oxidizing properties, its ability to complex certain metal ions, and its detoxifier capacity of 3-hydroxykynurenine (3-HK), its brain precursor. However, little is still known about the role and mechanisms of action of XA in the central nervous system (CNS). Therefore, many research groups have recently investigated XA and its central functions extensively. The present paper critically reviews and discusses all major data related to XA properties and neuronal activities to contribute to the improvement of the current knowledge on XA's central roles and mechanisms of action. In particular, our data showed the existence of a specific G-protein-coupled receptor (GPCR) for XA localized exclusively in brain neurons exhibiting Ca2+-dependent dendritic release and specific electrophysiological responses. XA properties and central activities suggest a role for this compound in brain intercellular signaling. Indeed, XA stimulates cerebral dopamine (DA) release contrary to its structural analog, kynurenic acid (KYNA). Thus, KYNA/XA ratio could be fundamental in the regulation of brain glutamate and DA release. Cerebral XA may also represent an homeostatic signal between the periphery and several brain regions where XA accumulates easily after peripheral administration. Therefore, XA status in certain psychoses or neurodegenerative diseases seems to be reinforced by its brain-specific properties in balance with its formation and peripheral inputs.

Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition

Injuries to skeletal muscle are among the most common injuries in civilian and military populations, accounting for nearly 60% of extremity injuries. The standard of care for severe extremity injury has been focused upon limb salvage procedures and the utilization of tissue grafts or orthotics in conjunction with rehabilitation to avoid amputation. Nonetheless, many patients have persistent strength and functional deficits that permanently impact their quality of life. Preclinical and clinical studies have shown that partial restoration of functional skeletal muscle tissue following injury can be achieved by the implantation of a biologic scaffold composed of extracellular matrix (ECM). These favorable outcomes are mediated, at least in part, through local immunomodulation. The mechanisms underlying this immunomodulatory effect, however, are poorly understood. The present study investigates a potential mechanistic driver of the immunomodulatory effects; specifically, the effect of selected ECM components upon inflammation resolution and repair. Results show that the host response to skeletal muscle injury is profoundly altered and functional recovery decreased in il33−/− mice compared to age- and sex-matched wildtype counterparts by 14 days post-injury. Results also show that IL-33, contained within matrix-bound nanovesicles (MBV), supports skeletal muscle regeneration by regulating local macrophage activation toward a pro-remodeling phenotype via canonical and non-canonical pathways to improve functional recovery from injury compared to untreated il33−/− counterparts. Taken together, these data suggest that MBV and their associated IL-33 cargo represent a novel homeostatic signaling mechanism that contributes to skeletal muscle repair.

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass

Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.