The Molecular Foundations of High Heart Rates: Sarcomeric Protein Adaptations.

Abstract

From shrews to whales, mammals exhibit a range of heart rates that varies more than 100-fold. Whilst the fundamental processes of cardiac contraction are conserved, the repertoire of contractile proteins of the sarcomere must be optimized to each species' operating heart rate range. For genes expressed in both cardiac and skeletal muscle types, such as myosin heavy chain and titin, paralog switching and alternative splicing provide a versatile toolkit that flexibly and reversibly modulates sarcomeric proteins. These interchangeable strategies enable precise functional adaptation without requiring permanent sequence changes. However, because these genes are shared across striated muscle types, fixed sequence mutations can inevitably affect both cardiac and skeletal muscle, restricting evolutionary innovation. In contrast, regulatory proteins with heart-specific paralogs-such as cardiac troponin I and cardiac myosin binding protein C-have evolved with fewer constraints, accumulating mutations that fine-tune their interactions and functions specifically for the myocardium.