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

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 PKC alpha in the Z-disc of skeletal muscle. Studies of Ldb3(Ala165Val/+) 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 PKC alpha 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. Pathak et al. identify LDB3, a striated muscle PDZ-LIM protein, as a signaling adaptor in a major mechanosensor assembly through interactions with filamin C, HSPA8, and PKC alpha. When LDB3 is mutated, PKC alpha and TSC2-mTOR mediated homeostasis is impaired, leading to protein aggregation myopathy.

Automated summary

This research demonstrates that the LDB3 protein regulates mechanical stress signaling through interactions with filamin C, HSPA8, and PKC alpha. Mutations in LDB3 lead to early aggregation of filamin C and its chaperones at the muscle Z-disc, ultimately causing protein aggregation myopathy.