Aslamy, A. | Search bioRxiv

bioRxiv2026

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Initial Insights into the Dynamic Human Responses to Exercise

The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs robustly improved several physiological parameters (i.e., VO2peak, muscular strength). Temporal biospecimen (blood, muscle, and adipose) collections and processing coupled to the acute exercise bouts were highly successful. In most cases, over 90% success was achieved for blood, muscle, and adipose samples. Endurance and resistance exercise induced distinct acute and chronic physiological responses, which provide a framework to interrogate the molecular basis for health adaptations to these two popular exercise modalities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/705347v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@554ee9org.highwire.dtl.DTLVardef@afb28dorg.highwire.dtl.DTLVardef@f381cdorg.highwire.dtl.DTLVardef@cef19c_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets

IntroductionType 1 diabetic human islet {beta}-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet {beta}-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown. MethodsBiochemical studies, qPCR, proteomics, and immuno-confocal microscopy were conducted to determine the underlying protective mechanisms of DOC2b in {beta}-cells. DOC2b- enriched or-depleted primary islets (human and mouse) and {beta}-cell lines challenged with or without proinflammatory cytokines, global DOC2b heterozygous knockout mice subjected to multiple-low-dose-streptozotocin (MLD-STZ), were used for these studies. ResultsA significant elevation of stress-induced CXCL10 mRNA was observed in DOC2b- depleted {beta}-cells and primary mouse islets. Further, DOC2b enrichment markedly attenuated cytokine-induced CXCL10 levels in primary non-diabetic human islets and {beta}-cells. DOC2b enrichment also reduced total-NF-{kappa}B p65 protein levels in human islets challenged with T1D mimicking proinflammatory cytokines. IKK{beta}, NF-{kappa}B p65, and STAT-1 are capable of associating with DOC2b in cytokine-challenged {beta}-cells. DOC2b enrichment in cytokine-stressed human islets and {beta}-cells corresponded with a significant reduction in activated and total IKK{beta} protein levels. Total I{kappa}B{beta} protein was increased in DOC2b-enriched human islets subjected to acute cytokine challenge. Cytokine-induced activated and total STAT-1 protein and mRNA levels were markedly reduced in DOC2b-enriched human islets. Intriguingly, DOC2b also prevents ER-stress-IKK{beta} and STAT-1 crosstalk in the rat INS1-832/13 {beta}-cell line. ConclusionThe mechanisms underpinning the protective effects of DOC2b involve attenuation of IKK{beta}-NF-{kappa}B p65 and STAT-1 signaling, and reduced CXCL10 expression. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/629540v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1b9d0acorg.highwire.dtl.DTLVardef@32db73org.highwire.dtl.DTLVardef@e5645aorg.highwire.dtl.DTLVardef@1f7619_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗