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Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

The design space of E(3)-equivariant atom-centred interatomic potentials

Molecular dynamics simulation is an important tool in computational materials science and chemistry, and in the past decade it has been revolutionized by machine learning. This rapid progress in machine learning interatomic potentials has produced a number of new architectures in just the past few years. Particularly notable among these are the atomic cluster expansion, which unified many of the earlier ideas around atom-density-based descriptors, and Neural Equivariant Interatomic Potentials (NequIP), a message-passing neural network with equivariant features that exhibited state-of-the-art accuracy at the time. Here we construct a mathematical framework that unifies these models: atomic cluster expansion is extended and recast as one layer of a multi-layer architecture, while the linearized version of NequIP is understood as a particular sparsification of a much larger polynomial model. Our framework also provides a practical tool for systematically probing different choices in this unified design space. An ablation study of NequIP, via a set of experiments looking at in- and out-of-domain accuracy and smooth extrapolation very far from the training data, sheds some light on which design choices are critical to achieving high accuracy. A much-simplified version of NequIP, which we call BOTnet (for body-ordered tensor network), has an interpretable architecture and maintains its accuracy on benchmark datasets.

Enhanced paracrine action of FGF21 in stromal cells delays thymic aging

Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1+ TECs, accelerated thymic aging, suggesting regulation of TECs by FGF21 is partially required for thymic lymphopoiesis. These findings establish that paracrine FGF21 improves thymic function and delays immune aging.

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