Biology subjects

Abreu, P.

Publications and source records attributed to Abreu, P..

3 recordsLinked to original sources

bioRxiv2025

Proteomic and Metabolomic Profiling Nominates Druggable Targets and Biomarkers forPulmonary Arterial Hypertension-Associated Myopathy and Exercise Intolerance

BackgroundPulmonary arterial hypertension (PAH) is a rare but debilitating condition that causes exercise intolerance and ultimately death. Skeletal muscle derangements contribute to depressed exercise capacity in PAH, but the mechanisms underlying muscle dysfunction including the changes in muscle biology based on fiber type are understudied. MethodsWe evaluated exercise capacity, muscle histopathology, mitochondrial density, mitochondrial proteomics, and metabolomics/lipidomics of quadriceps (predominately fast fibers) and soleus (predominately slow fibers) muscles in the monocrotaline (MCT) rat model of PAH. ResultsMCT rats exhibited impaired exercise capacity. Surprisingly, there were divergent atrophic and metabolic remodeling in the quadriceps and soleus muscles of MCT rats. In the quadriceps, there was a mild atrophic response only in type II fibers. In contrast, both type I and II fibers atrophied in the soleus. Both muscles exhibited fibrotic infiltration, but mitochondrial density was reduced in the quadriceps only. Mitochondrial proteomics and tissue metabolomics/lipidomics profiling demonstrated the two muscles exhibited distinct responses as the quadriceps had impairments in oxidative phosphorylation/fat metabolism and storage of triacylglycerides. However, the soleus showed signs of proteasome deficiencies and alterations in phosphatidylcholine/phosphatidylethanolamine homeostasis. Finally, profiling of metabolites/lipids in the serum identified potential novel biomarkers of exercise intolerance in PAH including the dimethylarginine pathway, cysteine, and triacylglycerides. ConclusionOur data suggests differential cachectic and metabolic responses occur in PAH-induced myopathy. We nominate mitochondrial biogenesis and proteasome activation as potential druggable targets for PAH-myopathy.

systems biology↗

bioRxiv2019

Adult Muscle Stem Cell Self-Renewal Induced by Endurance Exercise is Mediated by Inhibition of Mitochondrial Oxygen Consumption

Skeletal muscle stem cells (satellite cells) are well known to participate in regeneration and maintenance of the tissue over time. Studies have shown increases in the number of satellite cells after exercise, but their functional role in endurance training remains unexplored. Here, we found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibers compared to controls, as well as lower inflammation and fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers. Control satellite cells had morphologies suggestive of early differentiation, while endurance exercise enhanced myogenic colony formation. The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O2 consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (three days after injury), O2 consumption was equal in control and exercised cells. Surprisingly, inhibition of mitochondrial O2 consumption was sufficient to enhance muscle stem cell self-renewal characteristics in vitro. Moreover, transplanted muscle satellite cells from exercised mice or cells with reduced mitochondrial respiration promoted a significant reduction in inflammation compared to controls. We propose that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, and which is associated with a more favorable muscular response to injury.

biochemistry↗

bioRxiv2019

Mitochondrial Morphology Regulates Organellar Ca2+ Uptake and Changes Cellular Ca2+ Homeostasis

Changes in mitochondrial size and shape have been implicated in several physiological processes, but their role in mitochondrial Ca2+ uptake regulation and overall cellular Ca2+ homeostasis is largely unknown. Here we show that modulating mitochondrial dynamics towards increased fusion through expression of a dominant negative form of the fission protein DRP1 (DRP1-DN) markedly increased both mitochondrial Ca2+ retention capacity and Ca2+ uptake rates in permeabilized C2C12 cells. Similar results were seen using the pharmacological fusion-promoting M1 molecule. Conversely, promoting a fission phenotype through the knockdown of the fusion protein mitofusin 2 (MFN2) strongly reduced mitochondrial Ca2+ uptake speed and capacity in these cells. These changes were not dependent on modifications in inner membrane potentials or the mitochondrial permeability transition. Implications of mitochondrial morphology modulation on cellular calcium homeostasis were measured in intact cells; mitochondrial fission promoted lower basal cellular calcium levels and lower endoplasmic reticulum (ER) calcium stores, as measured by depletion with thapsigargin. Indeed, mitochondrial fission was associated with ER stress. Additionally, the calcium-replenishing process of store-operated calcium entry (SOCE) was impaired in MFN2 knockdown cells, while DRP1-DN-promoted fusion resulted in faster cytosolic Ca2+ increase rates. Overall, our results show a novel role for mitochondrial morphology in the regulation of mitochondrial Ca2+ uptake, which impacts on cellular Ca2+ homeostasis.

cell biology↗