NRIP is a novel Z-disc protein to activate calmodulin signaling for skeletal muscle contraction and regeneration

Abstract

Nuclear receptor interaction protein (NRIP, also known as DCAF6 and IQWD1) is a calcium-dependent calmodulin binding protein (Ca2+/CaM). In this study, we found that NRIP is a novel Z-disc protein in skeletal muscle. NRIP knockout mice (NRIP KO) were generated and found to have reduced muscle strength, susceptibility to fatigue and impaired adaptive exercise performance. The mechanisms of NRIP-regulated muscle contraction depend on NRIP being downstream of calcium signaling, where it stimulates phosphorylation of both calcineurin-nuclear factor of activated T-cells, cytoplasmic 1 (CaN-NFATc1) and calmodulin-dependent protein kinase II (CaMKII) through interaction with CaM, resulting in the induction of slow myosin gene expression and mitochondrial activity, and balancing of Ca2+ homeostasis of the internally stored Ca2+ of the sarcoplasmic reticulum. Moreover, NRIP KO mice have delayed regenerative capacity. The amount of NRIP can be enhanced after muscle injury and is responsible for muscle regeneration, coupled with the increased expression of myogenin, desmin and embryonic myosin heavy chain for myogenesis, as well as myotube formation. In conclusion, NRIP is a novel Z-disc protein important for skeletal muscle strength and regenerative capacity.