Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCalpha and TSC2-mTOR downregulation

Authors
P Pathak, Y Blech-Hermoni, K Subedi ET AL

Lab
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA

Journal
Communications Biology

Abstract
Mechanical stress induced by contractions constantly threatens the integrity of muscle Z[1]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 PKC_ 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 PKCalpha and TSC2-mTOR, two important signaling pathways regulating protein sta[1]bility and disposal of damaged cytoskeletal components at a major mechanosensor hub in the Z-disc of skeletal muscle.

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)