1. Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism
- Author
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Blondelle, Jordan, Marrocco, Valeria, Clark, Madison, Desmond, Patrick, Myers, Stephanie, Nguyen, Jim, Wright, Matthew, Bremner, Shannon, Pierantozzi, Enrico, Ward, Samuel, Estève, Eric, Sorrentino, Vincenzo, Ghassemian, Majid, and Lange, Stephan
- Subjects
Biochemistry and Cell Biology ,Medical Physiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Brain Disorders ,Rare Diseases ,Intellectual and Developmental Disabilities (IDD) ,Aetiology ,2.1 Biological and endogenous factors ,Musculoskeletal ,Animals ,Cytoskeletal Proteins ,Female ,Humans ,Male ,Mice ,Mice ,129 Strain ,Mice ,Knockout ,Muscle Development ,Muscle ,Skeletal ,Protein Serine-Threonine Kinases ,Proteome ,Rho Guanine Nucleotide Exchange Factors ,Sarcoglycans ,Sarcolemma ,Sarcoplasmic Reticulum ,Experimental models of disease ,Mechanisms of disease ,Membrane proteins ,Molecular medicine ,Biological sciences ,Biomedical and clinical sciences - Abstract
Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems.
- Published
- 2019