Abstract
Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins have been proposed to function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKCα in the Z-disc of skeletal muscle. Studies of Ldb3Ala165Val/+ mice indicate that the myopathy-associated LDB3 p.Ala165Val mutation triggers early aggregation of filamin C and its chaperones at muscle Z-disc before aggregation of the mutant protein. The mutation causes protein aggregation and eventually Z-disc myofibrillar disruption by impairing PKCα and TSC2-mTOR, two important signaling pathways regulating protein stability and disposal of damaged cytoskeletal components at a major mechanosensor hub in the Z-disc of skeletal muscle.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Animals
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Autophagy
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Disease Models, Animal
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Down-Regulation
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Filamins / metabolism
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HSC70 Heat-Shock Proteins / metabolism
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LIM Domain Proteins / genetics*
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Mechanotransduction, Cellular*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle Contraction
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Muscle Strength
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Muscle, Skeletal / enzymology*
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Muscle, Skeletal / pathology
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Muscle, Skeletal / physiopathology
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Myopathies, Structural, Congenital / enzymology*
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Myopathies, Structural, Congenital / genetics
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Myopathies, Structural, Congenital / pathology
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Myopathies, Structural, Congenital / physiopathology
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Point Mutation*
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Protein Aggregates
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Protein Aggregation, Pathological
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Protein Kinase C-alpha / genetics
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Protein Kinase C-alpha / metabolism*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Tuberous Sclerosis Complex 2 Protein / genetics
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Tuberous Sclerosis Complex 2 Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Filamins
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HSC70 Heat-Shock Proteins
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Hspa8 protein, mouse
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LIM Domain Proteins
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Ldb3 protein, mouse
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Protein Aggregates
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 2 Protein
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Prkca protein, mouse
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Protein Kinase C-alpha