Biology subjects

Damen, F.

Publications and source records attributed to Damen, F..

3 recordsLinked to original sources

bioRxiv2023

Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation

BackgroundAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. MethodsRight atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. ResultsIn human patients with AF, PPP1R12C expression was increased two-fold versus SR controls (P=2.0x10-2, n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation (P=1.4x10-6, n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9x10-2 and 6.7x10-3 respectively, n=8,8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls (P=5.0x10-6, n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls (P=1.8x10-2 and 4.1x10-2 respectively, n= 6,6,5). ConclusionsAF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

molecular biology↗

bioRxiv2019

Evolution of the gastrointestinal tract morphology and plasticity in cave-adapted Mexican tetra, Astyanax mexicanus

The gastrointestinal tract has evolved in numerous ways to allow animals to optimally assimilate energy from different foods. The morphology and physiology of the gut is plastic and can be greatly altered by diet in some animals. In this study, we investigated the evolution and plasticity of gastrointestinal tract morphology by comparing laboratory-raised cave- and river-adapted forms of the Mexican tetra, Astyanax mexicanus, reared under different dietary conditions. In the wild, river-dwelling populations (surface fish) consume plants and insects throughout the year, while cave-dwelling populations (cavefish) live in a perpetually dark environment and depend on nutrient-poor food brought in by bats or seasonal floods. We found that multiple cave populations converged on a reduced number of digestive appendages called pyloric caeca and that some cave populations have a lengthened gut while others have a shortened gut. Moreover, we identified differences in how gut morphology and proliferation respond to diet between surface fish and cavefish. Using a combination of quantitative genetic mapping, population genetics, and RNA sequencing, we found that changes to the molecular and genetic pathways that influence cell proliferation, differentiation, and immune system function may underlie evolution of the cavefish gut.

evolutionary biology↗

bioRxiv2019

Genetic architecture underlying changes in carotenoid accumulation during the evolution of the Blind Mexican cavefish, Astyanax mexicanus

Carotenoids are yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and therefore limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed. Astyanax mexicanus is a species of fish with river-adapted (surface) and multiple cave-adapted populations (i.e. Tinaja, Pachon, Molino). Cavefish exhibit regressive features such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here we show that unlike surface fish, Tinaja and Pachon cavefish accumulate carotenoids in the visceral adipose tissue (VAT). Carotenoid accumulation is not observed in Molino cavefish indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci mapping and RNA sequencing to investigate genetic changes associated with this trait. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into un-pigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishes A. mexicanus as a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.\n\nResearch HighlightsO_LICavefish accumulate carotenoids in the visceral adipose tissue (VAT)\nC_LIO_LIGenetic mapping reveals candidate genes associated with yellow VAT\nC_LIO_LICarotenoid accumulation is linked with decreased expression of carotenoid-processing genes\nC_LI

evolutionary biology↗