Sarcolipin deletion in mdx mice impairs calcineurin signalling and worsens dystrophic pathology. (21st August 2018)

• Record Type: Journal Article
• Authors: Fajardo, Val A; Chambers, Paige J; Juracic, Emma S; Rietze, Bradley A; Gamu, Daniel; Bellissimo, Catherine; Kwon, Frenk; Quadrilatero, Joe; Russell Tupling, A
• Is Part Of: Human molecular genetics. Volume 27:Number 23(2018:Dec. 01)
• Page Start: 4094
• Page End: 4102
• Publication Date: 2018-08-21
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddy302
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy affecting 1 in 3500 live male births. Although there is no cure for DMD, therapeutic strategies aimed at enhancing calcineurin signalling and promoting the slow fibre phenotype have shown promise in mdx mice, which is the classical mouse model for DMD. Sarcolipin (SLN) is a small protein that regulates the sarco(endo)plasmic reticulum Ca 2+ -ATPase pump and its expression is highly upregulated in dystrophic skeletal muscle. We have recently shown that SLN in skeletal muscle amplifies calcineurin signalling thereby increasing myofibre size and the slow fibre phenotype. Therefore, in the present study we sought to determine the physiological impact of genetic Sln deletion in mdx mice, particularly on calcineurin signalling, fibre-type distribution and size and dystrophic pathology. We generated an mdx / Sln- null ( mdx / Sln KO ) mouse colony and hypothesized that the soleus and diaphragm muscles from these mice would display blunted calcineurin signalling, smaller myofibre sizes, an increased proportion of fast fibres and worsened dystrophic pathology compared with mdx mice. Our results show that calcineurin signalling was impaired in mdx / Sln KO mice as indicated by reductions in utrophin, stabilin-2 and calcineurin expression. In addition, mdx / Sln KO muscles contained smaller myofibres, exhibited a slow-to-fast fibre-type switch that corresponded with reduced expression of mitochondrial proteins and displayed a worsened dystrophic pathology compared with mdx muscles. Altogether, our findings demonstrate a critical role for SLN upregulation in dystrophic muscles and suggest that SLN can be viewed as a potential therapeutic target.