Desminopathy-Associated TLR4 Dysregulation and Mitochondrial Alterations: Potential Effects of Natural Compounds in a Translational Model
(2026)
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- This thesis presents the first exploration of cellular inflammation via the TLR4 pathway, together with mitochondrial dynamics and morphology, in the genetic muscle disease desminopathy—a condition that currently has no cure, lacks disease-specific treatments, and is marked by gaps in our understanding of its pathophysiology. To address these gaps, this thesis specifically investigates TLR4 inflammatory signaling in skeletal muscle (the primary tissue affected by desmin mutations) and in peripheral blood mononuclear cells (PBMCs) as a model of systemic immune response. In addition, we characterize the clinical and functional phenotype of patients with desminopathy to integrate molecular findings with disease presentation. Additionally, this thesis includes the first case report in the scientific literature suggesting potential modulation of the TLR4 pathway and mitochondrial dynamics/morphology in desminopathy by a cocoa-derived natural compound. Consistent with this translational direction, we also conducted in vitro experimental work using a C2C12 cell culture model to determine the effect of another natural compound, i.e. urolithin A, on TLR4 signaling and mitochondrial dynamics/morphology. The selected compound was chosen because prior evidence has shown effects on health markers (from higher expression of PINK1, AMPKα, PGC1α until higher skeletal muscle endurance) in humans, as well as in animal and cellular models. Taken together, this work outlines a potential research avenue involving natural compound–based interventions aimed at investigating—and ultimately limiting—the progression of desminopathy.
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Tapia-Curimil, G. (2026). Desminopathy-Associated TLR4 Dysregulation and Mitochondrial Alterations: Potential Effects of Natural Compounds in a Translational Model. https://hdl.handle.net/2078.5/274118