Type IV Collagen Is Essential for Proper Function of Integrin-Mediated Adhesion in Drosophila Muscle Fibers

Abstract

Congenital muscular dystrophy (CMD), a subgroup of myopathies is a genetically and clinically heterogeneous group of inherited muscle disorders and is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen (COL4A1) mutations have recently been identified in patients with intracerebral, vascular, renal, ophthalmologic pathologies and congenital muscular dystrophy, consistent with diagnoses of Walker–Warburg Syndrome or Muscle–Eye–Brain disease. Morphological characteristics of muscular dystrophy have also been demonstrated Col4a1 mutant mice. Yet, several aspects of the pathomechanism of COL4A1-associated muscle defects remained largely uncharacterized. Based on the results of genetic, histological, molecular, and biochemical analyses in an allelic series of Drosophila col4a1 mutants, we provide evidence that col4a1 mutations arise by transitions in glycine triplets, associate with severely compromised muscle fibers within the single-layer striated muscle of the common oviduct, characterized by loss of sarcomere structure, disintegration and streaming of Z-discs, indicating an essential role for the COL4A1 protein. Features of altered cytoskeletal phenotype include actin bundles traversing over sarcomere units, amorphous actin aggregates, atrophy, and aberrant fiber size. The mutant COL4A1-associated defects appear to recapitulate integrin-mediated adhesion phenotypes observed in RNA-inhibitory Drosophila. Our results provide insight into the mechanistic details of COL4A1-associated muscle disorders and suggest a role for integrin-collagen interaction in the maintenance of sarcomeres.

Advanced Glycation End-Products in Skeletal Muscle Aging

“…Furthermore, there is an increase in aberrant glycation cross-links that stiffens all collagens and other ECM components, which dysregulates quiescent muscle stem cells and muscle force transmission [ 65 , 72 , 86 ]. Collagen type IV, which forms a net-like structure in the basal lamina, serves as a scaffolding protein for the laminins and other cell-anchoring proteins [ 87 ]. Old age increases collagen type IV levels while decreasing the ability of muscle to regulate collagen type IV following injury [ 85 , 88 ].…”

Gene protein sequence evolution can predict the rapid divergence of ovariole numbers inDrosophila

“…Remarkably, among the nine somatic cell types, these genes were nearly exclusively upregulated in the TFs (TFa or TFp, or both) and/or the SHm cells. We note that vkg and Col4a1 play roles in basement membrane formation (Yasothornsrikul et al 1997; Kiss et al 2019), and that SHm cells lay the membrane that separates the TFs for ovariole development (King 1970; Slaidina et al 2020). Given the crucial roles of these cell types in determining ovariole number (King, Aggarwal et al 1968, Sarikaya and Extavour 2015), the rapid evolution of these five genes may partially underlie ovariole number divergence between species (King et al 1968; Sarikaya and Extavour 2015) in the melanogaster subgroup (table 4).…”

“…Among the nine somatic cell types, these genes were nearly exclusively upregulated in the TFs (TFa or TFp, or both) and/or the SHm cells. We note that vkg and Col4a1 play roles in basement membrane formation (Yasothornsrikul, et al 1997;Kiss, et al 2019), and that SHm cells lay the membrane that separates the TFs for ovariole development (King 1970;Slaidina, et al 2020).…”

Regulation of morphogen pathways by a Drosophila chondroitin sulfate proteoglycan Windpipe

“…Therefore, simultaneous loss of wdp and Sulf1 might disrupt a step in this pathway or normal muscle development in these organs. Alternatively, ovulation might be impaired by physical disruption in wdp; Sulf1 , such as the failure of the formation of a tubular structure that connects the ovary and oviduct ( Deady et al, 2015 ; Kiss et al, 2019 ). Drosophila ovulation and flight muscle development will be additional useful model systems to study the functions of HS and CS.…”