Resident macrophage-dependent immune cell scaffolds drive anti-bacterial defense in the peritoneal cavity.

Peritoneal immune cells reside unanchored within the peritoneal fluid in homeostasis. Here, we examined the mechanisms that control bacterial infection in the peritoneum using a mouse model of abdominal sepsis following intraperitoneal Escherichia coli infection. Whole-mount immunofluorescence and confocal microscopy of the peritoneal wall and omentum revealed that large peritoneal macrophages (LPMs) rapidly cleared bacteria and adhered to the mesothelium, forming multilayered cellular aggregates composed by sequentially recruited LPMs, B1 cells, neutrophils, and monocyte-derived cells (moCs). The formation of resident macrophage aggregates (resMφ-aggregates) required LPMs and thrombin-dependent fibrin polymerization. E. coli infection triggered LPM pyroptosis and release of inflammatory mediators. Resolution of these potentially inflammatory aggregates required LPM-mediated recruitment of moCs, which were essential for fibrinolysis-mediated resMφ-aggregate disaggregation and the prevention of peritoneal overt inflammation. Thus, resMφ-aggregates provide a physical scaffold that enables the efficient control of peritoneal infection, with implications for antimicrobial immunity in other body cavities, such as the pleural cavity or brain ventricles.

DIDO is necessary for the adipogenesis that promotes diet-induced obesity.

The prevalence of overweight and obesity continues to rise in the population worldwide. Because it is an important predisposing factor for cancer, cardiovascular diseases, diabetes mellitus, and COVID-19, obesity reduces life expectancy. Adipose tissue (AT), the main fat storage organ with endocrine capacity, plays fundamental roles in systemic metabolism and obesity-related diseases. Dysfunctional AT can induce excess or reduced body fat (lipodystrophy). Dido1 is a marker gene for stemness; gene-targeting experiments compromised several functions ranging from cell division to embryonic stem cell differentiation, both in vivo and in vitro. We report that mutant mice lacking the DIDO N terminus show a lean phenotype. This consists of reduced AT and hypolipidemia, even when mice are fed a high-nutrient diet. DIDO mutation caused hypothermia due to lipoatrophy of white adipose tissue (WAT) and dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome supported Dido1 control of the cellular lipid metabolic process. We found that, by controlling the expression of transcription factors such as C/EBPα or PPARγ, Dido1 is necessary for adipocyte differentiation, and that restoring their expression reestablished adipogenesis capacity in Dido1 mutants. Our model differs from other lipodystrophic mice and could constitute a new system for the development of therapeutic intervention in obesity.

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis.

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established. Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients. Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

p38γ is essential for cell cycle progression and liver tumorigenesis.

The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease.

Myeloid p38 activation maintains macrophage-liver crosstalk and BAT thermogenesis through IL-12-FGF21 axis.

Obesity features excessive fat accumulation in several body tissues and induces a state of chronic low-grade inflammation that contributes to the development of diabetes, steatosis, and insulin resistance. Recent research has shown that this chronic inflammation is crucially dependent on p38 pathway activity in macrophages, suggesting p38 inhibition as a possible treatment for obesity comorbidities. Nevertheless, we report here that lack of p38 activation in myeloid cells worsens high-fat diet-induced obesity, diabetes, and steatosis. Deficient p38 activation increases macrophage IL-12 production, leading to inhibition of hepatic FGF21 and reduction of thermogenesis in the brown fat. The implication of FGF21 in the phenotype was confirmed by its specific deletion in hepatocytes. We also found that IL-12 correlates with liver damage in human biopsies, indicating the translational potential of our results. Our findings suggest that myeloid p38 has a dual role in inflammation and that drugs targeting IL-12 might improve the homeostatic regulation of energy balance in response to metabolic stress.

p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1.

During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.

Prevention of taxane chemotherapy-induced nail changes and peripheral neuropathy by application of extremity cooling: a prospective single-centre study with intrapatient comparison.

PURPOSE: Common side effects of taxane chemotherapy are nail toxicity and peripheral neuropathy (CIPN) causing severe impact on the quality of life. Different methods of cryotherapy to prevent these side effects have been tested. We investigated the use of machine-controlled cooling of hands and feet to reduce nail toxicity and CIPN in patients receiving taxane chemotherapy. METHODS: Patients receiving Docetaxel (planned dose ≥ 300 mg/m2) or Paclitaxel (planned dose ≥ 720 mg/m2 - ) in the adjuvant or palliative setting of different cancers were included. The dominant hand and foot were cooled to approximately 10 °C using the Hilotherapy machine. The contralateral hand and foot were used as intrapatient comparison. The primary endpoint was the occurrence of any CIPN due to paclitaxel or nail toxicity due to Docetaxel. Both the intention to treat population (ITT) and the per protocol population (PPP) were analyzed. RESULTS: A total of 69 patients, 21 treated with Docetaxel and 48 with Paclitaxel, were included at our centre between 08/2020 and 08/2022. Nail toxicity due to Docetaxel was overall not significantly improved by cooling in the ITT or PPP but a significant benefit across visits was found for the ITT. CIPN due to Paclitaxel was numerically better in the ITT and significantly better in the PPP. A significant benefit of cooling on CIPN occurrence across visits was found for the ITT and the PPP. Cooling was very well tolerated. CONCLUSION: Cooling of hands and feet has a clinically meaningful impact on reducing occurrence of CIPN and nail toxicity on treatment with taxanes. Effects are more significant over time and are dose dependent. TRIAL REGISTRATION NUMBER: 2020-00381. Date of registration. 24th February 2020.

JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma.

Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.

p38α blocks brown adipose tissue thermogenesis through p38δ inhibition.

Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue. Here, using mice that are deficient in p38α specifically in adipose tissue (p38αFab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38αFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ. Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δ Fab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI). Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes.

p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen-activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.

Social dominance, but not parasite load, affects sperm quality and sperm redox status in house sparrows.

Sperm performance is an important component of male reproductive success. However, sperm production is costly and males need to optimize their investment in sperm quality versus the somatic traits involved in mating success, e.g. their social status. As oxidative stress affects both sperm performance and somatic functions, it has been hypothesized to mediate such a trade-off. According to the oxidation-based soma/germline trade-off hypothesis, dominant males should favour the antioxidant protection of their somatic tissues, and subordinate males should favour the antioxidant protection of their sperm. We tested this hypothesis by experimentally infecting wild-caught house sparrows Passer domesticus with Coccidia Isopora sp., an internal parasite known to deplete antioxidant resources. We predicted that (i) increased parasite load affects sperm oxidative status and sperm performance and that (ii) males with experimentally high parasite load adjust the antioxidant protection of their soma versus their sperm according to their social status. Despite a 5400% increase in parasite load, sperm performance and somatic and spermatic oxidative status remained unaffected, irrespective of male social status. Nevertheless, males increased their sperm performance over time, a pattern mirrored by an increase in the antioxidant protection of their sperm. Moreover, males at the lower end of the hierarchy always produced sperm of lower velocity, suggesting that they were constrained and privileged their soma over their germline. To conclude, high parasite loads do not necessarily affect sperm performance and oxidative status. In contrast, social hierarchy and the relative investment in soma versus sperm antioxidant protection are determinants of sperm performance.

Is sperm morphology functionally related to sperm swimming ability? A case study in a wild passerine bird with male hierarchies.

BACKGROUND: Sexual selection continues after copulation via either sperm competition or cryptic female choice, and favors sperm traits that maximize sperm competitiveness. Both sperm swimming velocity and longevity are important determinants of the outcome of sperm competition. Theoretically, sperm morphology can influence sperm velocity at least in three different non-exclusive ways: (i) longer sperm may generate more propelling thrust, (ii) bigger midpieces may produce more energy, and/or (iii) larger flagella or mid-pieces relative to the head size may compensate for the drag forces around the head. A growing number of studies have investigated the relationship of sperm morphology with sperm performance, which remains equivocal at both the inter- and intra-specific levels. Here, we used House Sparrows to test the functional relationship between sperm morphology with sperm velocity and longevity. Based on a previous study showing that sperm swimming ability covaries with social rank, we predicted that -if a functional relationship exists-1) sperm morphology should differ across social ranks, and 2) correlations between sperm morphology and sperm velocity and/or sperm longevity should be constant across social ranks. RESULTS: We found no differences in sperm morphology across social ranks. Moreover, we found that sperm morphology may be correlated with sperm velocity, but such relationship varied across social ranks. This result contradicts the hypothesis of a functional relationship between sperm morphology and sperm performance. Finally, after experimentally manipulating social ranks, we observed that relationships between sperm morphology and sperm velocity and/or sperm longevity disappeared or changed direction. CONCLUSIONS: We suggest that in species with internal fertilization, while sperm morphology is likely constrained by the morphology of the female sperm storage organs, selection may act upon physiological traits that enhance sperm performance. Hence, these two selection forces could decouple sperm performance from sperm morphology.

Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1.

The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic-pituitary-thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic-pituitary-thyroid axis represents an important target of metabolic signaling by JNK1.

Social dominance explains within-ejaculate variation in sperm design in a passerine bird.

BACKGROUND: Comparative studies suggest that sperm competition exerts stabilizing selection towards an optimal sperm design - e.g., the relative size and covariation of different sperm sections or a quantitative measure of sperm shape - that maximizes male fertility, which results in reduced levels of within-male variation in sperm morphology. Yet, these studies also reveal substantial amounts of unexplained within-ejaculate variance, and the factors presiding to the maintenance of such within-male variation in sperm design at the population level still remain to be identified. Sperm competition models predict that males should progressively invest more resources in their germline as their mating costs increase, i.e., the soma/germline allocation trade-off hypothesis. When access to fertile females is determined by social dominance, the soma/germline allocation trade-off hypothesis predicts that dominant males should invest less in the control of spermatogenesis. Hence, dominance should positively correlate with within-male variance in sperm design. RESULTS: In support of this hypothesis, we found that dominant house sparrow males produce ejaculates with higher levels of within-ejaculate variation in sperm design compared to subordinate males. However, after experimentally manipulating male social status, this pattern was not maintained. CONCLUSIONS: Our results suggest that males might control variation in sperm design according to their social status to some extent. Yet, it seems that such within-ejaculate variation in sperm design cannot be rapidly adjusted to a new status. While variation in sperm design could result from various non-exclusive sources, we discuss how strategic allocation of resources to the somatic vs. the germline functions could be an important process shaping the relationship between within-male variation in sperm design and social status.

Oxidative stress affects sperm performance and ejaculate redox status in subordinate house sparrows.

Oxidative stress is the result of random cellular damage caused by reactive oxygen species that leads to cell death, ageing or illness. Most physiological processes can result in oxidative stress, which in turn has been identified as a major cause of infertility. In promiscuous species, the fertilizing ability of the ejaculate partly determines the male reproductive success. When dominance determines access to fertile females, theory predicts that lower ranking males should increase resource investment into enhancing ejaculate quality. We hypothesized that subordinate males should thus prioritize antioxidant protection of their ejaculates to protect them from oxidative stress. We put this hypothesis to the test by chronically dosing wild house sparrows with diquat (∼1 mg kg-1), a herbicide that increases pro-oxidant generation. We found that, although they increased their antioxidant levels in the ejaculate, diquat-treated males produced sperm with reduced velocity. Importantly, and contrary to our hypothesis, males at the bottom of the hierarchy suffered the largest reduction in sperm velocity. We suggest that resource access hinders individuals' ability to cope with environmental hazards. Our results point at oxidative stress as a likely physiological mechanism mediating ejaculate quality, while individual ability to access resources may play a role in constraining the extent to which such resources can be allocated into the ejaculate.

Ecotoxicological assessment of the impact of nitrate (NO(3)(¯)) on the European endangered white-clawed crayfish Austropotamobius italicus (Faxon).

Field studies and laboratory experiments were conducted to assess the impact of elevated nitrate (NO(3)(¯)) concentrations on the European endangered white-clawed crayfish Austropotamobius italicus (Faxon) in the Henares River Basin (Central Spain), within an area that is vulnerable to nitrate pollution. Two sampling surveys were carried out in the summer of 2009 and 2011 to collect freshwater crayfish at eight sampling sites along this vulnerable area. The invasive read-swamp crayfish Procambarus clarkii (Girard) was the only collected crayfish species. Nitrate toxicity experiments however showed that A. italicus is one of the most tolerant species to nitrate toxicity. Although the food consumption was the most sensitive endpoint to nitrate toxicity (followed by the escape response and mortality), the no-observed-effect concentration (NOEC) for this endpoint after 14 days of exposure to nitrate was as high as 100mg NO(3)(¯)N/l, with some crayfish being still alive after fourteen days of exposure to a nominal nitrate concentration of 800mg NO(3)(-)N/l. Besides, a safe concentration of nitrate for A. italicus, along with its respective 95% confidence limits, were estimated to be 68.5 (22.4-187) mg (NO(3)(¯)N/l. Overall we conclude that elevated nitrate concentrations would not be responsible for the absence of white-clawed crayfish in the Henares River Basin. Other environmental factors, particularly the presence of P. clarkii and its fungal pathogen, would be major causes.

Are bone targeted agents still useful in times of immunotherapy? The SAKK 80/19 BTA pilot study.

Background: Patients with bone metastases from solid tumors often have additional treatment with bone targeted agents (BTAs) to avoid symptomatic skeletal events (SSEs) such as clinically significant pathological fracture leading toradiation therapy or surgery to the bone, spinal cord compression, or hypercalcemia. The absolute value of BTA treatment in the era of immunotherapy (IO) is unknown. Methods: Patients with bone metastases treated with immunotherapy within the Alpine Tumor Immunology Registry were compared based on whether they received an additional BTA such as denosumab or zoledronic acid. The primary endpoint was time to first SSE. Continuous data were summarized as median and range, categorical data using frequency counts and percentages. Kaplan-Meier estimates were used to describe and visualize the effect of categorical variables. Results: One hundred and ninety-seven patients with bone metastases and treatment with immunotherapy such as nivolumab (48 %), pembrolizumab (40 %), atezolizumab (12 %), ipilimumab (9 %) and other immunotherapy (5 %) were included. The most frequent tumor types were lung cancer (50 %), malignant melanoma (11 %), renal cell cancer (10 %) and bladder cancer (9 %), respectively. One hundred and twenty-two patients (62 %) received a BTA treatment (91 % denosumab). The median treatment duration of a BTA was 178 days (min: 1 day, max: 2010 days). Out of the 197 patients, 47 (24 %) experienced at least one SSE, 100 (51 %) had bone pain. Ten of the 122 patients (8 %) receiving a BTA developed osteonecrosis of the jaw (ONJ). The percentage of patients without an SSE at fixed time points was higher if treated with a BTA (e.g., at 6 months, 92 % [95 % CI: 84 % - 96 %] versus 88 % [95 % CI: 77 % - 94 %]), but no significant difference in time to first SSE (HR 0.69; 95 % CI 0.34-1.39, log-rank p = 0.29) or time to first bone pain (HR: 0.85; 95 % CI: 0.51-1.43, p = 0.54) between these two groups could be detected. There were differences in OS between patients treated with a BTA and patients not treated with a BTA (HR: 1.46; 95 % CI: 1.01-2.10, p = 0.043). Conclusion: No significant difference in time to first SSE or bone pain was observed between patients who have received a BTA or not when treated with immunotherapy. Based on these retrospective results the indication of BTAs to reduce SSEs in cancer patients under treatment with immunotherapy needs further evaluation.

Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma.

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.

Remodeling p38 signaling in muscle controls locomotor activity via IL-15.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.