{Reference Type}: Journal Article
{Title}: Improved mitochondrial function in the hearts of sarcolipin-deficient dystrophin and utrophin double-knockout mice.
{Author}: Mareedu S;Fefelova N;Galindo CL;Prakash G;Mukai R;Sadoshima J;Xie LH;Babu GJ;
{Journal}: JCI Insight
{Volume}: 9
{Issue}: 9
{Year}: 2024 Apr 2
{Factor}: 9.484
{DOI}: 10.1172/jci.insight.170185
{Abstract}: Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin double-knockout (mdx:utrn-/-) mice in a sarcolipin (SLN) heterozygous-knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium. Germline reduction of SLN expression in mdx:utrn-/- mice improved cardiac sarco/endoplasmic reticulum (SR) Ca2+ cycling, reduced cardiac fibrosis, and improved cardiac function. At the cellular level, reducing SLN expression prevented mitochondrial Ca2+ overload, reduced mitochondrial membrane potential loss, and improved mitochondrial function. Transmission electron microscopy of myocardial tissues and proteomic analysis of mitochondria-associated membranes showed that reducing SLN expression improved mitochondrial structure and SR-mitochondria interactions in dystrophic cardiomyocytes. These findings indicate that SLN upregulation plays a substantial role in the pathogenesis of cardiomyopathy and that reducing SLN expression has clinical implications in the treatment of DMD cardiomyopathy.