Abstract
Ankyrin repeat and kinase domain containing 1 (ANKK1) gene has been widely related to neuropsychiatry disorders. The localization of ANKK1 in neural progenitors and its correlation with the cell cycle has suggested its participation in development. However, ANKK1 functions still need to be identified. Here, we have further characterized the ANKK1 localization in vivo and in vitro, by using immunolabeling, quantitative real-time PCR and Western blot in the myogenic lineage. Histologic investigations in mice and humans revealed that ANKK1 is expressed in precursors of embryonic and adult muscles. In mice embryos, ANKK1 was found in migrating myotubes where it shows a polarized cytoplasmic distribution, while proliferative myoblasts and satellite cells show different isoforms in their nuclei and cytoplasm. In vitro studies of ANKK1 protein isoforms along the myogenic progression showed the decline of nuclear ANKK1-kinase until its total exclusion in myotubes. In adult mice, ANKK1 was expressed exclusively in the Fast-Twitch muscles fibers subtype. The induction of glycolytic metabolism in C2C12 cells with high glucose concentration or treatment with berberine caused a significant increase in the ANKK1 mRNA. Similarly, C2C12 cells under hypoxic conditions caused the increase of nuclear ANKK1. These results altogether show a relationship between ANKK1 gene regulation and the metabolism of muscles during development and in adulthood. Finally, we found ANKK1 expression in regenerative fibers of muscles from dystrophic patients. Future studies in ANKK1 biology and the pathological response of muscles will reveal whether this protein is a novel muscle disease biomarker.
Highlights
Ankyrin repeat and kinase domain containing 1 (ANKK1) protein belongs to the receptorinteracting protein (RIP) kinase family [1]
ANKK1 in myogenic precursors and muscle fibers subtypes with glycolytic metabolism myotubes derived from both muscle anlagen of caudal (Fig 1C) and occipital regions (Fig 1D)
This study shows for the first time that ANKK1 expression is not restricted to neural precursors and postmitotic neural cells but extends to the myogenic lineage
Summary
Ankyrin repeat and kinase domain containing 1 (ANKK1) protein belongs to the receptorinteracting protein (RIP) kinase family [1]. RIP kinases are involved in cell survival and death [1,2], as well as in differentiation processes in a broad variety of tissues [2,3,4]. The gene that codes for ANKK1 is located in a 512 Kb cluster along with neural cell adhesion molecule 1 (NCAM1), dopamine receptor D2 (DRD2) and tetratricopeptide repeat domain 12 gene (TTC12) genes [9]. The NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2)shows a conserved synteny and neighborhood suggesting the coordinated functioning of these proteins by co-regulation of gene expression [9]
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