Cardiac phenotype of Duchenne Muscular Dystrophy: insights from cellular studies

Abstract

Dilated cardiomyopathy is a serious and almost inevitable complication of Duchenne Muscular Dystrophy, a devastating and fatal disease of skeletal muscle resulting from the lack of functional dystrophin, a protein linking the cytoskeleton to the extracellular matrix. Ultimately, it leads to congestive heart failure and arrhythmias resulting from both cardiac muscle fibrosis and impaired function of the remaining cardiomyocytes. Here we summarize findings obtained in several laboratories, focusing on cellular mechanisms that result in degradation of cardiac functions in dystrophy.

Diagram 1. Damage and cell death pathways in Dystrophy

The abnormally high activity of several signaling pathways, such as ROS/RNS, hyperphosphorylation and Ca²⁺ signals, triggers mitochondrial damage pathways which ultimately may culminate in apoptotic or necrotic cell death.

Diagram 2. Signaling pathways involved in Dystrophy

The diagram shows the main building blocks of cardiac Ca²⁺ signaling and EC-coupling. This is combined with the sources, pathways and targets of the pathomechanisms relevant for alterations of Ca²⁺ signaling in dystrophic cardiomyopathy. Green lines: pathways of oxidative and nitrosative signals (ROS/RNS). Red lines: pathways of protein phosphorylation signals. Solid lines depict pivotal and dashed lines depict secondary pathways. Dotted lines indicate additional targets of phosphorylation. Abbreviations not explained in the review: Cav3: caveolin-3; NaC: voltage-dependent Na⁺ channel. LTCC: L-type Ca²⁺ channel. AC: adenylate cyclase; MR: membrane ruptures; HNX: mitochondrial proton-sodium exchanger; MCU: mitochondrial Ca²⁺ uniporter; ANT: mitochondrial translocase.