Biology subjects

Wolan, D.

Publications and source records attributed to Wolan, D..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions

Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction, and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations of mitochondrial morphology suggest mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumor-conditioned media (TCM) could promote mPT, and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibers increased mROS and Caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion co-localization, and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle wasting disorders.

physiology↗

bioRxiv2025

The Secreted Metabolite Isopentenyladenine from Faecalibacterium prausnitzii Mitigates Gut Inflammation

Colonic microbiome dysbiosis is correlated with inflammatory bowel disease (IBD), and depletion of the commensal bacterium Faecalibacterium prausnitzii (F. prausnitzii) is routinely observed in the metagenomic analyses of IBD patient microbiome samples. F. prausnitzii is likely beneficial to hosts, as oral administration of F. prausnitzii strain A2-165 has anti-inflammatory properties in murine models of colitis. Previous studies attribute the anti-inflammatory effects of F. prausnitzii A2-165 to production of the short-chain fatty acid butyrate, as well as a 15 kDa protein known as microbial anti-inflammatory molecule (MAM). Here, we verified that oral dosing of strain A2-165 protects against DSS-induced murine colitis and further show the aqueous-soluble secreted fraction of overnight cultures from a collection of F. prausnitzii strain inhibit inflammatory signatures, including the activation of the hosts NF-{kappa}B pathway, production of IL-8, and differentiation of naive T cells into the TH17 lineage. We find that MAM is secreted in extracellular vesicles; however, MAM-containing vesicles do not have anti-inflammatory properties in our collection of assays and suggests that MAM is likely not a direct contributor. Untargeted and targeted mass spectrometry metabolomics analyses on the soluble anti-inflammatory secretome yielded several unique F. prausnitzii metabolites, including isopentenyladenine. We demonstrated isopentenyladenine independently modulates host cellular signaling and immune responses and suggests this newly identified metabolite with human immunomodulatory properties may be useful towards the discovery of IBD-focused therapeutics.

microbiology↗

bioRxiv2019

A selective and rapid cell-permeable inhibitor of human caspase-3

The individual roles and overlapping functionalities the twelve human caspases have during apoptosis and other cellular processes remain poorly resolved primarily due to a lack of chemical tools. Here we present a new selective caspase-3 inhibitor, termed Ac-ATS010-KE, with rapid and irreversible binding kinetics. Relative to previously designed caspase-3-selective molecules that have tremendously abated inhibitory rates and thus limited use in biological settings, the improved kinetics of Ac-ATS010-KE permit its use in a cell-based capacity. We demonstrate that Ac-ATS010-KE prevents apoptosis with comparable efficacy to the general caspase inhibitor Ac-DEVD-KE and surprisingly does so without side-chain methylation. This observation is in contrast to the well-established peptide modification strategy typically employed for improving cellular permeability. Ac-ATS010-KE protects against extrinsic apoptosis, which demonstrates the utility of a thiophene carboxylate leaving group in biological settings, challenges the requisite neutralization of free carboxylic acids to improve cell permeability, and provides a tool-like compound to interrogate the role of caspase-3 in a variety of cellular processes.

biochemistry↗