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 through increased endotrophin, a collagen VI-derived signaling molecule linked to fibrotic remodeling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to a critical function in muscle physiology. However, the functional role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodeled T-tubules, suggesting a possible role in tubular structure and Ca²⁺ dynamics.

To investigate 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 organization were unchanged, but echocardiography demonstrated reduced systolic function. Consistent with this, isolated trabeculae from Col6a1^-/- hearts generated significantly less peak stress, confirming impaired contractile force at the tissue level. Paradoxically, isolated cardiomyocytes from the Col6a1^-/- rat had increased Ca²⁺ transient amplitude and increased sarcoplasmic reticulum Ca²⁺ load that would be expected to increase force. β-adrenergic stimulation further increased Ca²⁺ transient amplitude and was associated with diastolic Ca²⁺ release events in Col6a1^-/- cardiomyocytes. Furthermore, β-adrenergic stimulation of Col6a1^-/- trabeculae exhibited spontaneous contractions, indicating an increased susceptibility to arrhythmic activity.

Together, these results indicate collagen VI has a role in both force transduction and Ca²⁺ cycling in the heart.