Fig. 8. The evolution and function of the N-terminal extension of cardiac TnI.

The TnI isoforms genes emerged early in the evolution of vertebrate striated muscles. The evolution of a cardiac-specific isoform of TnI and the emergence of the N-terminal extension and PKA phosphorylation sites coincide with the emergence of lungs to increase oxygenation and metabolic rate in cardiac muscle. The N-terminal extension with the PKA phosphorylation sites of cardiac TnI functions to regulate heart function, which could be a key step to enable early tetrapods to move to land where increased energetic demand requires adaptation to allow for higher calcium sensitivity and ultimately stronger contraction. A restrictive proteolytic cleavage that selectively removes the N-terminal extension of cardiac TnI occurs in in mammalian hearts as a physiological adaptation to chronic heart failure, implicating a benefit to transiently reverse the function of cardiac TnI to an ancestral state like that of bony fishes.