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Lipidomics of Tango2 Deficient and Wildtype Zebrafish Muscle Tissue

ABSTRACT: Rhabdomyolysis is a clinical emergency characterized by severe muscle damage, resulting in the release of intracellular muscle components which leads to myoglobinuria and in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors that are linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy, and cardiac arrhythmia. The underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we demonstrate that the loss of Tango2 in zebrafish results in growth defects, early lethality, and increased susceptibility of muscle defects similar to TANGO2 patients. Detailed analyses of skeletal muscle revealed defects in the sarcoplasmic reticulum and mitochondria at the onset of disease development. The sarcoplasmic reticulum (SR) constitutes the primary lipid biosynthesis site and regulates calcium handling in skeletal muscle to control excitation-contraction coupling. Tango2 deficient SR exhibits increased sensitivity to calcium release that was partly restored by inhibition of Ryr1-mediated Ca2+ release in skeletal muscle. Using lipidomics, we identified alterations in the glycerolipid state of tango2 mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and have increased our understanding of the impacts of specific defects on predisposition to environmental triggers in TANGO2-related disorders.

ORGANISM(S): Danio Rerio Zebrafish

TISSUE(S): Muscle

DISEASE(S): Myopathy

SUBMITTER: Emily Wallace

PROVIDER: ST002398 | MetabolomicsWorkbench | Wed Dec 07 00:00:00 GMT 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Mansur A, Joseph R, Jean-Beltran PM, Udeshi ND, Pearce C, Jiang H, Iwase R, McNamara E, Widrick J, Perez C, Ravenscroft G, Cole PA, Carr SA, Gupta VA. 2022 Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases including myopathies and muscular atrophy. However, the mechanistic understanding of specific components on the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein result in a severe form of congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive, remains poorly understood. To characterize the KLHL40-regulated ubiquitin modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of klhl40 mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy and biosynthetic metabolic processes and vesicle trafficking. Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a negative regulator of ER-Golgi retrograde trafficking through ubiquitin-mediated protein degradation of secretion associated Ras related GTPase1a (Sar1a). In KLHL40 deficient muscle, defects in ER exit site vesicle formation alter Golgi compartment and downstream transport of extracellular cargo proteins, resulting in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients.

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Lipidomics of Tango2 Deficient and Wildtype Zebrafish Muscle Tissue

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