The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.
© 2025. The Author(s).

Aging negatively impacts tissue repair, particularly in skeletal muscle, where the regenerative capacity of muscle stem cells (MuSCs) diminishes with age. Although aerobic exercise is known to attenuate skeletal muscle atrophy, its specific impact on the regenerative and repair capacity of MuSCs remains unclear.
Mice underwent moderate-intensity continuous training (MICT) from 9 months (aged + Ex-9M) or 20 months (aged + Ex-20M) to 25 months, with age-matched (aged) and adult controls. Histological examinations and MuSC transplantation assays assessed aerobic exercise effects on MuSC function and muscle regeneration. CCN2/connective tissue growth factor modulation (overexpression and knockdown) in MuSCs and AICAR supplementation effects were explored.
Aged mice displayed significantly reduced running duration (65.33 ± 4.32 vs. 161.9 ± 1.29 min, mean ± SD, P < 0.001) and distance (659.17 ± 103.64 vs. 3058.28 ± 46.26 m, P < 0.001) compared with adults. This reduction was accompanied by skeletal muscle weight loss and decreased myofiber cross-sectional area (CSA). However, MICT initiated at 9 or 20 months led to a marked increase in running duration (142.75 ± 3.14 and 133.86 ± 20.47 min, respectively, P < 0.001 compared with aged mice) and distance (2347.58 ± 145.11 and 2263 ± 643.87 m, respectively, P < 0.001). Additionally, MICT resulted in increased skeletal muscle weight and enhanced CSA. In a muscle injury model, aged mice exhibited fewer central nuclear fibres (CNFs; 266.35 ± 68.66/mm2), while adult, aged + Ex-9M and aged + Ex-20M groups showed significantly higher CNF counts (610.82 ± 46.76, 513.42 ± 47.19 and 548.29 ± 71.82/mm2, respectively; P < 0.001 compared with aged mice). MuSCs isolated from aged mice displayed increased CCN2 expression, which was effectively suppressed by MICT. Transplantation of MuSCs overexpressing CCN2 (Lenti-CCN2, Lenti-CON as control) into injured tibialis anterior muscle compromised regeneration capacity, resulting in significantly fewer CNFs in the Lenti-CCN2 group compared with Lenti-CON (488.07 ± 27.63 vs. 173.99 ± 14.28/mm2, P < 0.001) at 7 days post-injury (dpi). Conversely, knockdown of CCN2 (Lenti-CCN2shR, Lenti-NegsiR as control) in aged MuSCs improved regeneration capacity, significantly increasing the CNF count from 254.5 ± 26.36 to 560.39 ± 48.71/mm2. Lenti-CCN2 MuSCs also increased fibroblast proliferation and exacerbated skeletal muscle fibrosis, while knockdown of CCN2 in aged MuSCs mitigated this pattern. AICAR supplementation, mimicking exercise, replicated the beneficial effects of aerobic exercise by mitigating muscle weight decline, enhancing satellite cell activity and reducing fibrosis.
Aerobic exercise effectively reverses the decline in endurance capacity and mitigates muscle atrophy in aged mice. It inhibits CCN2 secretion from senescent MuSCs, thereby enhancing skeletal muscle regeneration and preventing fibrosis in aged mice. AICAR supplementation mimics the beneficial effects of aerobic exercise.
© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.

ABSTRACT Increased endothelial cell (EC) proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). The underlying mechanism and disease relevance of this abnormal cell proliferative state of the ECs remain unknown. Here, we report the identification of a CDK6-driven mechanism of cell cycle progression deregulation directly involved in EC proliferation and HHT vascular pathology. Specifically, HHT mouse liver ECs exhibited defects in their cell cycle control characterized by a G1/S checkpoint bypass and acceleration of cell cycle speed. Phosphorylated retinoblastoma (p-RB1)—a marker of G1/S transition through the restriction point—significantly accumulated in ECs of HHT mouse retinal AVMs and HHT patient skin telangiectasias. Mechanistically, ALK1 loss of function increased the expression of key restriction point mediators, and treatment with palbociclib or ribociclib, two CDK4/6 inhibitors, blocked p-RB1 increase and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and slowed down endothelial cell cycle speed and EC proliferation. Specific deletion of Cdk6 in ECs was sufficient to protect HHT mice from AVM pathology. Thus, CDK6-mediated endothelial cell cycle acceleration controls EC proliferation in AVMs and is a central determinant of HHT pathogenesis. We propose that clinically approved CDK4/6 inhibitors have repurposing potential in HHT.

Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but challenges with dosing or side effects such as bleeding limit clinical application. In this study, we demonstrate that suramin, a widely available polyanionic drug, completely neutralizes the toxic effects of individual histones, but not citrullinated histones from neutrophil extracellular traps. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sublethal doses of histones in vivo. Suramin also prevented histone-induced lung endothelial cell cytotoxicity in vitro and lung edema, intra-alveolar hemorrhage, and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.
Copyright © 2023 by The American Association of Immunologists, Inc.

The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two major subtypes of pancreatic β cells based on histone mark heterogeneity (βHI and βLO). βHI cells exhibit ∼4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. βHI and βLO cells also differ in size, morphology, cytosolic and nuclear ultrastructure, epigenomes, cell surface marker expression, and function, and can be FACS separated into CD24+ and CD24- fractions. Functionally, βHI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates βHI/βLO ratio in vivo, suggesting that control of β cell subtype identity and ratio is at least partially uncoupled. Both subtypes are conserved in humans, with βHI cells enriched in humans with type 2 diabetes. Thus, epigenetic dosage is a novel regulator of cell subtype specification and identifies two functionally distinct β cell subtypes.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.