Aberrant Caspase Activation in Laminin-α2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity

Abstract

Background:Mutations in the LAMA2 gene encoding laminin-α2 cause congenital muscular dystrophy Type 1A (MDC1A), a severe recessive disease with no effective treatment. Previous studies have shown that aberrant activation of caspases and cell death through a pathway regulated by BAX and KU70 is a significant contributor to pathogenesis in laminin-α2-deficiency.Objectives:To identify mechanisms of pathogenesis in MDC1A.Methods:We used immunocytochemical and molecular studies of human myogenic cells and mouse muscles—comparing laminin-α2-deficient vs. healthy controls—to identify mechanisms that regulate pathological activation of caspase in laminin-α2-deficiency.Results:In cultures of myogenic cells from MDC1A donors, p53 accumulated in a subset of nuclei and aberrant caspase activation was inhibited by the p53 inhibitor pifithrin-alpha. Also, the p53 target BBC3 (PUMA) was upregulated in both MDC1A myogenic cells and Lama2–/– mouse muscles. In addition, studies with sirtuin inhibitors and SIRT1 overexpression showed that caspase activation in MDC1A myotubes was inversely related to sirtuin deacetylase activity. Caspase activation in laminin-α2-deficiency was, however, not associated with increased phosphorylation of p38 MAPK.Conclusions:Aberrant caspase activation in MDC1A cells was mediated both by sirtuin deacetylase activity and by p53. Interventions that inhibit aberrant caspase activation by targeting sirtuin or p53 function could potentially be useful in ameliorating MDC1A.

<p>Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy</p>

“…Various microRNAs are dysregulated in LAMA2 MD, and their expression can certainly be modulated as an approach 143,144. Polyamines,145 decorin,146 Ku70,147 p53, and sirtuin148 are also starting to be recognized as potential therapeutic targets. Managing diet149 or bone marrow transplantation150 may also be options, but follow-up studies into these are lacking.…”

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

“…Mouse models for LAMA2-CMD have provided an excellent platform for studies of signaling events. Signaling cascades associated with apoptosis, inflammation, metabolism, regeneration, protein turnover, and fibrosis (GAPDH-Siah1-CBP/p300-p53, Akt, TGFβ, NFκB, p53, JAK/STAT, to mention a few) have been shown to be affected in laminin α2 chain-deficient murine muscle (Girgenrath et al, 2004(Girgenrath et al, , 2009Erb et al, 2009;Carmignac et al, 2011a,b;Kumar et al, 2011;Meinen et al, 2012;Elbaz et al, 2015;de Oliveira et al, 2014;Mehuron et al, 2014;Accorsi et al, 2015;Fontes-Oliveira et al, 2017;Gawlik et al, 2017Gawlik et al, , 2019Nunes et al, 2017;Pasteuning-Vuhman et al, 2018;Yoon et al, 2018). Additionally, microarray, RNA-sequencing and proteomic technologies were applied to study murine LAMA2-CMD dystrophic muscle and provided a global overview of the gene and protein expression changed upon laminin α2 chaindeficiency (van Lunteren et al, 2006;Hager et al, 2008;de Oliveira et al, 2014;Kemaladewi et al, 2017;Moreira Soares Oliveira et al, 2018;Yanay et al, 2019).…”