The absence of collagen VI reduces systolic function but paradoxically increases Ca2+ release in the rat heart

Collagen VI has recently been strongly linked to poor outcomes in heart failure with preserved ejection fraction through increased endotrophin, a collagen VI-derived signalling molecule linked to fibrotic remodelling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to critical function in muscle physiology. However, the role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodelled T-tubules, suggesting a possible role in tubular structure and Ca2+ dynamics. To test this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1-/-) was generated in the rat. T-tubule structure and ryanodine receptor cluster organisation were unchanged, but echocardiography demonstrated reduced systolic function. Paradoxically, isolated cardiomyocytes from the Col6a1-/- rat had increased Ca2+ transient amplitude and increased sarcoplasmic reticulum Ca2+ load. {beta}-adrenergic stimulation further increased Ca2+ transient amplitude and was associated with diastolic Ca2+ release events in Col6a1-/- cardiomyocytes. The disturbed Ca2+ dynamics are remarkedly similar to defects found in cardiac myocytes of the MDX mouse that has non-functional dystrophin protein. Together, these data suggest that collagen VI contributes to regulation of Ca2+ signalling in the heart through its linkage to the dystrophin-glycoprotein complex.