Key result
Rat-human β-myosin chimera increases in vitro motility velocity ~2-fold over wild-type human myosin.
Why the study?
Heart rate and maximum striated muscle contraction velocity are inversely related to species size, requiring adaptations such as slower contracting muscles as mammals evolve to different sizes.
Evolutionary adaptation of heart rate to body size in mammals is mediated by a small set of amino acid variations in β-cardiac myosin that adjust contraction velocity.
Preclinical chimera data remain hypothesis-generating; leaves open whether these sites can tune human cardiac velocity or heart rate.
Heart rate and the maximum velocity of contraction of striated muscle are inversely related to species size. As mammals evolve to different sizes, adaptations are required such as slower contracting heart and skeletal muscles. Analysis of the motor domain of β-myosin from 67 mammals from two clades identifies 14 sites, out of 800, strongly associated with body mass (p<0.01) but not with the clade (p>0.05). Nine of these sites were mutated in the human β-myosin to make it resemble the rat sequence. Biochemical analysis revealed that the rat-human β-myosin chimera functioned like the native rat myosin with a two fold increase in both motility and in the rate of ADP release from the actin.myosin cross-bridge (the step that limits contraction velocity). Both clades use the same small set of amino acids to adjust contraction velocity, suggesting a limited number of ways in which velocity can be manipulated.
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Johnson et al. (2019) studied Evolutionary adaptation of cardiac contraction velocity (n=67). Rat-human beta-myosin chimera (9 amino acid substitutions) vs. Native human wild-type beta-myosin was evaluated on In vitro motility velocity (almost 2-fold increase). A rat-human β-myosin chimera incorporating nine rat-specific amino acid substitutions increased in vitro motility velocity almost two-fold (from 0.49 to 0.9 μm/s) compared to wild-type human myosin.
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