Impact of single-nucleotide polymorphisms at the TP53-binding and responsive promoter region of BCL2 gene in modulating the phenotypic variability of LGMD2C patients

Abstract

Apoptosis of skeletal muscle fibers is a well-known event occurring in patients suffering from muscular dystrophies. In this study, we hypothesized that functional polymorphisms in genes involved in the mitochondrial apoptotic pathway might modulate the apoptotic capacity underlying the muscle loss and contributing to intrafamilial and interfamilial variable phenotypes in LGMD2C (Limb Girdle Muscular Dystrophy type 2C) patients sharing the same c.521delT mutation in SGCG gene. Detection of apoptosis was confirmed on muscle biopsies taken from LGMD2C patients using the TUNEL method. We genotyped then ten potentially functional SNPs in TP53, BCL-2 and BAX genes involved in the mitochondrial apoptotic pathway. Potential genotype-dependent Bcl-2 and p53 protein expressed in skeletal muscle was investigated using western blot and ELISA assays. The result showed that muscle cells carrying the TP53-R72R and TP53-16 bp del/del genotypes displayed an increased p53 level which could be more effective in inducing apoptosis by activation of the pro-apoptotic gene expression. In addition, the BCL2-938 AA genotype was associated with increased Bcl-2 protein expression in muscle from LGMD2C patients compared to -938CC genotype, while there was no evidence of significant difference in the BAX haplotype. Our findings suggest that increased Bcl-2 protein expression may counteract pro-apoptotic pathways and thus reduce the muscle loss. To the best of our knowledge, this is a pioneer study evaluating the role of apoptotic BCL-2 and TP53 genes in contributing to the phenotypic manifestation of c.521delT mutation in LGMD2C patients. Larger studies are needed to validate these findings.

ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle

“…Severe or prolonged stress leads to apoptosis via p53 activation of BAX5 and PUMA [71] as well as by repression of anti-apoptotic [72] and cell cycle [73] genes. Recently there have been reports of p53 upregulation in muscle being linked to muscle atrophy in Huntington’s disease [74] and LGMD2C [75]. Another case of p53 being associated with muscle weakness is ageing, in which there is a notable loss of muscle mass and an increase in adipose tissue resulting in a decline in skeletal muscle [76].…”

α-linolenic acid reduces TNF-induced apoptosis in C2C12 myoblasts by regulating expression of apoptotic proteins

“…21 Furthermore, in the mdx mouse model and in patients affected by Duchenne dystrophy, upregulation of pro-apoptotic proteins such as Bax and caspases were detected in myofibers, suggesting that under pathological conditions, these myofibers undergo apoptosis. 22-24 Apoptosis and decreased Bcl-2 expression were detected in other muscular dystrophies such as Limb Girdle MD type 2C, 25 and congenital MD type 1A. 26 …”

Three single nucleotide polymorphisms associated with type 2 diabetes mellitus in a Chinese population

“…The gene SGCG encodes gamma (γ)-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin (15). It was shown that the sarcoglycan null mice, which lacked the sarcoglycan complex in skeletal muscle and adipose tissue, were glucose-intolerant and exhibited whole body insulin due to impaired insulin-stimulated glucose uptake in skeletal muscles (16).…”