title: Myospryn is a calcineurin-interacting protein that negatively modulates slow-fiber-type transformation and skeletal muscle regeneration.
abstract: The calcium-calmodulin-regulated protein phosphatase calcineurin plays an important regulatory role in muscle differentiation, fiber-type determination, hypertrophy, and muscle regeneration. Because calcineurin functions in numerous processes in muscle, multiple mechanisms are likely necessary to ensure that the activity of this phosphatase is appropriately regulated. Here we demonstrate that the muscle-specific scaffolding protein myospryn modulates calcineurin signaling by inhibiting calcineurin-dependent transcriptional activity in C2C12 myoblasts through direct interaction with the enzyme via its noncanonical tripartite motif (TRIM-like). Consistent with these data, transgenic mice overexpressing both the TRIM-like domain of myospryn and constitutively active calcineurin displayed a severe attenuation in the ability of calcineurin to induce a slow-fiber phenotype. Furthermore, transgenic mice overexpressing the TRIM-like domain of myospryn displayed attenuated muscle regeneration after cardiotoxin-induced muscle injury. These results indicate that myospryn functions as a novel inhibitor of the calcineurin signaling pathway in skeletal muscle.
authors.affiliation: Department of Biology, Boston University, 24 Cummington St., Boston, MA 02215, USA.
authors.forename: Ondra M
authors.initials: OM
authors.lastname: Kielbasa
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Reynolds
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Wu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Snyder
authors.forename: Min Y
authors.initials: MY
authors.lastname: Cho
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Susan
authors.initials: S
authors.lastname: Kandarian
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D019556:COS Cells; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004179:Cobra Cardiotoxin Proteins / Q000633:toxicity; D003439:Crotoxin / Q000633:toxicity; D004338:Drug Combinations; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D011485:Protein Binding; D051381:Rats; D012038:Regeneration
chemical_list: D002352:Carrier Proteins; C484938:Cmya5 protein, mouse; D004179:Cobra Cardiotoxin Proteins; D004338:Drug Combinations; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C084936:cardiotoxin, crotoxin drug combination; D003439:Crotoxin; D019703:Calcineurin