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.
Keyphrases
- duchenne muscular dystrophy
- poor prognosis
- endoplasmic reticulum
- sentinel lymph node
- heart failure
- muscular dystrophy
- oxidative stress
- left ventricular
- long non coding rna
- binding protein
- early stage
- electron microscopy
- type diabetes
- lymph node
- cell proliferation
- reactive oxygen species
- adipose tissue
- signaling pathway
- radiation therapy
- early onset
- risk assessment
- metabolic syndrome
- high fat diet induced
- neoadjuvant chemotherapy
- dna repair
- climate change
- insulin resistance
- smoking cessation
- combination therapy
- high glucose
- locally advanced