Myopalladin promotes muscle growth through modulation of the serum response factor pathway

Abstract

Background Myopalladin (MYPN) is a striated muscle‐specific, immunoglobulin‐containing protein located in the Z‐line and I‐band of the sarcomere as well as the nucleus. Heterozygous MYPN gene mutations are associated with hypertrophic, dilated, and restrictive cardiomyopathy, and homozygous loss‐of‐function truncating mutations have recently been identified in patients with cap myopathy, nemaline myopathy, and congenital myopathy with hanging big toe. Methods Constitutive MYPN knockout (MKO) mice were generated, and the role of MYPN in skeletal muscle was studied through molecular, cellular, biochemical, structural, biomechanical, and physiological studies in vivo and in vitro. Results MKO mice were 13% smaller compared with wild‐type controls and exhibited a 48% reduction in myofibre cross‐sectional area (CSA) and significantly increased fibre number. Similarly, reduced myotube width was observed in MKO primary myoblast cultures. Biomechanical studies showed reduced isometric force and power output in MKO mice as a result of the reduced CSA, whereas the force developed by each myosin molecular motor was unaffected. While the performance by treadmill running was similar in MKO and wild‐type mice, MKO mice showed progressively decreased exercise capability, Z‐line damage, and signs of muscle regeneration following consecutive days of downhill running. Additionally, MKO muscle exhibited progressive Z‐line widening starting from 8 months of age. RNA‐sequencing analysis revealed down‐regulation of serum response factor (SRF)‐target genes in muscles from postnatal MKO mice, important for muscle growth and differentiation. The SRF pathway is regulated by actin dynamics as binding of globular actin to the SRF‐cofactor myocardin‐related transcription factor A (MRTF‐A) prevents its translocation to the nucleus where it binds and activates SRF. MYPN was found to bind and bundle filamentous actin as well as interact with MRTF‐A. In particular, while MYPN reduced actin polymerization, it strongly inhibited actin depolymerization and consequently increased MRTF‐A‐mediated activation of SRF signalling in myogenic cells. Reduced myotube width in MKO primary myoblast cultures was rescued by transduction with constitutive active SRF, demonstrating that MYPN promotes skeletal muscle growth through activation of the SRF pathway. Conclusions Myopalladin plays a critical role in the control of skeletal muscle growth through its effect on actin dynamics and consequently the SRF pathway. In addition, MYPN is important for the maintenance of Z‐line integrity during exercise and aging. These results suggest that muscle weakness in patients with biallelic MYPN mutations may be associated with reduced myofibre CSA and SRF signalling and that the disease phenotype may be aggravated by exercise.

Transcriptome Analysis of Differentially Expressed mRNA Related to Pigeon Muscle Development

“…Myopalladin (MYPN) is a striated muscle−specific, immunoglobulin−containing protein located in the Z−line and I−band of the sarcomere as well as the nucleus. MYPN promotes skeletal muscle growth by activating the serum response factor (SRF) pathway in muscle [ 21 ]. DKK3 is a stress−induced, renal tubular epithelia−derived, secreted glycoprotein (molecular mass, 38 kDa) [ 22 ] that induces tubulointerstitial fibrosis through its action on the canonical Wnt/ β −catenin signalling pathway [ 23 ].…”

Identification of Atrial Fibrillation-Associated Genes ERBB2 and MYPN Using Genome-Wide Association and Transcriptome Expression Profile Data on Left–Right Atrial Appendages

“…It is clear that numerous mutation loci in the gene are associated with hypertrophic, dilated, and restrictive cardiomyopathy ( Chen et al, 2017 ). One study demonstrated that MYPN knockout mice exhibited a 48% reduction in myofiber cross-sectional area and significantly increased fiber number, compared with wild-type controls ( Filomena et al, 2020 ). Our results showed that this gene is upregulated, suggesting that it may induce abnormal atrial myocardial fibrosis and therefore be associated with the occurrence of AF.…”

Morphological changes and functional circRNAs screening of rabbit skeletal muscle development

“…The GO terms of up-regulated DE-circRNAs (whose host genes were DEGs) in the fetus vs. child group were enriched in muscle development-related functions. For example, the host gene of novel_circ_0008909 is myopalladin (MYPN), which promotes muscle growth through modulation of the serum response factor pathway [ 22 ]. The down-regulated circRNAs in this group comprised novel_circ_0018533 whose host gene was zeste homolog 2 (EZH2).…”