Biology subjects

Sweeney, G.

Publications and source records attributed to Sweeney, G..

4 recordsLinked to original sources

bioRxiv2024

Adiponectin-receptor agonism prevents right ventricular tissue pathology in a mouse model of Duchenne muscular dystrophy

Cardiac fibrosis during Duchenne muscular dystrophy (DMD) arises from cellular damage and inflammation and is associated with myofibre hypertrophy and metabolic dysfunction. However, the extent to which these relationships develop across all 4 cardiac chambers, particularly during early-stage disease, remains unknown. Here, we discovered that very young D2.mdx mice exhibit fibrosis exclusively in the right ventricle (RV) and left atrium. Concurrent cardiomyocyte hypertrophy and disorganization in the RV were related to a highly specific inflammatory signature of increased infiltrating pro-inflammatory macrophages (CD11b+CD45+CD64+F4/80+CCR2+), myofibre mitochondrial-linked apoptosis, and reduced carbohydrate and fat oxidation. This relationship did not occur in the left ventricle. Short-term daily administration of a peptidomimetic adiponectin receptor agonist, ALY688, completely prevented RV fibrosis, myofibre hypertrophy, infiltrating macrophages and mitochondrial stress as well as left atrial fibrosis. Our discoveries demonstrate early-stage cardiac tissue pathology occurs in a chamber-specific manner and is prevented by adiponectin receptor agonism, thereby opening a new direction for developing therapies that prevent tissue remodeling during DMD. TeaserHeterogeneous distribution of fibrosis, inflammation and metabolic dysfunction across the heart is prevented by adiponectin receptor agonism in a mouse model of Duchenne muscular dystrophy.

physiology↗

bioRxiv2024

Selective disruption of Traf1/cIAP2 interaction attenuates inflammatory responses and limits sepsis and rheumatoid arthritis

Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an immune signaling adapter protein linked to increased susceptibility to rheumatoid arthritis (RA). TRAF1 has dual roles in regulating NF-{kappa}B and MAPK signaling: it promotes signaling through its association with cellular inhibitor of apoptosis 2 (cIAP2) downstream of certain tumor necrosis factor receptor (TNFR) family members but inhibits Toll-like receptor (TLR) signaling by limiting linear ubiquitination of key signaling proteins. Here, we identify a critical mutation in TRAF1 (V203A in humans, V196A in mice) that disrupts its interaction with cIAP2, leading to a significant reduction in TLR signaling and downstream inflammation in human and murine macrophages. We demonstrate that TRAF1 is recruited to the TLR4 complex and is indispensable for the recruitment of cIAP2, facilitating TAK1 phosphorylation and the activation of NF-{kappa}B and MAPK signaling pathways. Remarkably, mice harboring the TRAF1 V196A mutation are protected from LPS-induced septic shock and exhibit markedly reduced joint inflammation and disease severity in a collagen antibody-induced arthritis (CAIA) model of RA. These findings reveal a previously unrecognized and crucial role for the TRAF1/cIAP2 axis in promoting inflammation and offer a promising foundation for the development of novel therapeutic strategies for inflammatory conditions, such as sepsis and RA.

immunology↗

bioRxiv2023

Influence of preprocessing, distortion correction and cardiac triggering on the quality of diffusion MR images of spinal cord

Diffusion MRI of the spinal cord (SC) is susceptible to geometric distortion caused by field inhomogeneities, and prone to misalignment across time series and signal dropout caused by biological motion. Several modifications of image acquisition and image processing techniques have been introduced to overcome these artifacts, but their specific benefits are largely unproven and warrant further investigations. We aim to evaluate two specific aspects of image acquisition and processing that address image quality in diffusion studies of the spinal cord: susceptibility corrections to reduce geometric distortions, and cardiac triggering to minimize motion artifacts. First, we evaluate 4 distortion preprocessing strategies on 7 datasets of the cervical and lumbar SC and find that while distortion correction techniques increase geometric similarity to structural images, they are largely driven by the high-contrast cerebrospinal fluid, and do not consistently improve the geometry within the cord nor improve white-to-gray matter contrast. We recommend at a minimum to perform bulk-motion correction in preprocessing and posit that improvements/adaptations are needed for spinal cord distortion preprocessing algorithms, which are currently optimized and designed for brain imaging. Second, we design experiments to evaluate the impact of removing cardiac triggering. We show that when triggering is foregone, images are qualitatively similar to triggered sequences, do not have increased prevalence of artifacts, and result in similar diffusion tensor indices with similar reproducibility to triggered acquisitions. When triggering is removed, much shorter acquisitions are possible, which are also qualitatively and quantitatively similar to triggered sequences. We suggest that removing cardiac triggering for cervical SC diffusion can be a reasonable option to save time with minimal sacrifice to image quality.

neuroscience↗

bioRxiv2023

The adiponectin analogue ALY688-SR attenuates diaphragm fibrosis, atrophy and mitochondrial stress in a mouse model of Duchenne muscular dystrophy

Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analogue ALY688-SR prevents fibrosis and fibre type-specific atrophy in diaphragm of D2.mdx mice treated from days 7-28 of age. ALY688-SR also lowered IL-6mRNA but increased IL-6 and TGF-{beta} protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also lowered in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling and force generating properties during the very early stages of disease progression in D2.mdx mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR partially prevents fibrosis and atrophy in the more disease-apparent diaphragm of young D2.mdx mice in relation to lower mitochondrial redox stress. These results provide a foundation for the exploration of slow-release adiponectin-based therapies to prevent fibrosis and atrophy in Duchenne muscular dystrophy.

physiology↗