Key result
Rat collagen VI knockout reduces systolic function but paradoxically increases Ca2+ transients and arrhythmia susceptibility.
Why the study?
Collagen VI is linked to poor heart failure outcomes and is increased in remodeled T-tubules in HFrEF, but its functional role in the heart remains poorly understood.
Does the absence of collagen VI affect systolic function and Ca2+ cycling in the rat heart?
Does the absence of collagen VI affect systolic function and Ca2+ cycling in the rat heart?
Collagen VI plays a critical role in both force transduction and calcium cycling in the heart, with its absence leading to reduced systolic function and increased susceptibility to arrhythmic activity.
Collagen VI knockout impairs rat systolic function; leaves open its role as a therapeutic target in human HF.
Aim 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 Ca 2+ dynamics. Methods To investigate this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1 −/− ) was generated in the rat. Results 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 Ca 2+ transient amplitude and increased sarcoplasmic reticulum Ca 2+ load that would be expected to increase force. β‐adrenergic stimulation further increased Ca 2+ transient amplitude and was associated with diastolic Ca 2+ release events in Col6a1 −/− cardiomyocytes. Furthermore, β‐adrenergic stimulation of Col6a1 −/− trabeculae exhibited spontaneous contractions, indicating an increased susceptibility to arrhythmic activity. Conclusion Together, these results indicate collagen VI has a role in both force transduction and Ca 2+ cycling in the heart.
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Krstic et al. (2025) studied this question. Collagen VI knockout in rats reduced systolic function but paradoxically increased Ca2+ transient amplitude and susceptibility to arrhythmias.
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