MUSCLE MITOCHONDRIAL DYSFUNCTIONS AND SYSTEMIC LIPIDOMIC REMODELING IN SBMA

SBMA is increasingly recognized as a multisystem disorder in which neuromuscular degeneration is accompanied by profound metabolic alterations. Given their central role in energy homeostasis, membrane remodeling and cellular signaling, mitochondria and lipid metabolism may contribute to SBMA pathogenesis, but this remains not sufficiently explored. To investigate these aspects of the pathology, we carried out two distinct experimental approaches: cellular analyses in patient-derived induced pluripotent stem cell (iPSC) differentiated to skeletal muscle fibre and plasma lipidomic analysis of the KI-AR113Q mouse model. SBMA myoblasts displayed striking mitochondrial abnormalities, characterized by smaller and more rounded mitochondria, consistent with enhanced mitochondrial fragmentation. Quantitative morphometric analysis revealed a significant reduction in mitochondrial branching, indicating disruption of the mitochondrial network, and electron microscopy confirmed a marked decrease in mitochondrial size. Flow cytometry analysis assessment demonstrated a reduction in mitochondrial membrane potential, supporting impaired mitochondrial activity. Notably, ultrastructural analysis also revealed a decreased number and reduced size of lipid droplets, pointing to defective lipid storage and altered energy handling in SBMA muscle cells. Plasma lipidomic profiling in KI-AR113Q mice at different disease stages revealed presymptomatic alterations in long-chain, highly unsaturated phosphatidylcholines (PC 38:5; PC 40:8) enriched in essential fatty acids and arachidonic acid (20:3; 20:4; 20:5). With disease progression, lipid modifications emerged across multiple classes, including a decrease of long and highly unsaturated diacylglycerols, ceramides and lysophospholipids. These changes were accompanied by increased phosphatidylcholine-to-phosphatidylethanolamine (PC/PE) and triglyceride-to-cholesteryl ester (TAG/CE) ratios. Although these approaches address distinct biological levels, they could provide a complementary view of SBMA pathology. Cell-autonomous mitochondrial and lipid droplet dysfunctions in patient-derived muscle cells and progressive plasma lipid remodelling in the mouse model, independently highlight metabolic alterations as a central feature of SBMA. From a clinical and translational perspective these findings support plasma lipidomic profiles as potential accessible biomarkers of disease stage and progression and identify metabolic pathways as targets for therapeutic strategies aimed at improving muscle function in SBMA.