Thermal Stress Induces Long-Term Remodeling of Adipose Tissue and Is Associated with Systemic Dysfunction.

ABSTRACT: Severe burns are characterized by the magnitude and duration of the hypermetabolic response thereafter, and demarcated by the loss of lean body mass and catabolism of fat stores. The aim of the present study was to delineate the temporal and location-specific physiological changes to adipose depots and downstream consequences post-burn in a murine model of thermal injury. C57BL/6 mice were subjected to a 30% total body surface area burn and body mass, food intake, and tissue mass were monitored for various time points up until 60 days postinjury. Mitochondrial respirometry was performed using a Seahorse XF96 analyzer. Lipolytic markers and browning markers were analyzed via Western blotting and histology. A severe burn results in a futile cycle of lipolysis and white adipose tissue (WAT) browning, the sequelae of which include fat catabolism, hepatomegaly, and loss of body mass despite increased food intake. A dynamic remodeling of epididymal WAT was observed with acute and chronic increases in lipolysis. Moreover, we demonstrate that pathological browning of inguinal WAT persists up to 60 days post-burn, highlighting the magnitude of the ß-adrenergic response to thermal injury. Our data suggests that adipose depots have a heterogeneous response to burns and that therapeutic interventions targeting these physiological changes can improve outcomes. These data may also have implications for treating catabolic conditions such as cancer cachexia as well as developing treatments for obesity and type II diabetes.

Perivascular Inflammation in Pulmonary Arterial Hypertension.

Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.

Indirect regulation of HMGB1 release by gasdermin D.

The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1ß. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1ß secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1ß is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice.

KEY POINTS: Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia. A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined. Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre-clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia. At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind-like 1 protein from myonuclear foci and improved mRNA alternative splicing. ABSTRACT: Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild-type (SED-WT) mice, as well as sedentary human skeletal actin-long repeat animals, a murine model of DM1 myopathy (SED-DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX-DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70-85% decrease in the duration of myotonic discharges in muscles from EX-DM1 compared to SED-DM1 animals. The exercise-induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle-specific chloride channel (CLC-1) transcripts. CLC-1 protein content and sarcolemmal expression were lower in SED-DM1 versus SED-WT animals, but they were similar between SED-WT and EX-DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG)n foci-positive myonuclei and sequestered Muscleblind-like 1 (MBNL1). Our data indicate that chronic exercise-induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss-of-function, and alternative mRNA splicing.