Biology subjects

Rosales-Soto, G.

Publications and source records attributed to Rosales-Soto, G..

3 recordsLinked to original sources

bioRxiv2025

Chronic activation of a key exercise signal transducer, CaMKII, drives skeletal muscle aging and sarcopenia

Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy. These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.

physiology↗

bioRxiv2025

Cell type specific CaMKII activation patterns revealed by CaMKAR, a bioactivity reporter deployable in living cells

An accurate and precise mechanism for measuring CaMKII activity in living cells is invaluable in the search for effective and targeted CaMKII-based therapeutics. Here, we employ our recently published CaMKII Activity Reporter (CaMKAR) biosensor in order to investigate the spatiotemporal dynamics of CaMKII activation in three different types of cells - cardiac myocytes, skeletal myocytes, and neurons. In doing so, we found a greater rate of CaMKII activation in skeletal muscle compared to cardiac muscle and also delineated CaMKARs ability to measure discrete CaMKII activation events in the presence of individual action potentials. By modifying the original CaMKAR sequence, we generated sensors that can be localized to subcellular compartments and thereby preferentially detect the activity of specific spatially-distributed CaMKII isoforms. Finally, we utilized the live-cell data to generate mathematical models of CaMKII activation kinetics, both as an integrated function across multiple calcium transients and as discrete on-off events following individual depolarizations. By furthering our understanding of CaMKII activity profiles across cell types and within subcellular compartments, we hope to support development of CaMKII inhibitors that are optimally precise and potent.

molecular biology↗

bioRxiv2024

Scalable Hypothalamic Arcuate Neuron Differentiation from Human Pluripotent Stem Cells Suitable for Modeling Metabolic and Reproductive Disorders

The hypothalamus, composed of several nuclei, is essential for maintaining our bodys homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.

developmental biology↗