Shiver me titin! Elucidating titin's role in organism-level performance.

摘要

The frequency of oscillatory behaviors, like shivering, depends on the animal size and the properties of the muscles driving them. Titin and other muscular proteins play an important role in determining muscle properties, such as stiffness. Because the frequency of oscillatory behaviors depends on muscle properties, we predict that changes in titin's structure would affect these behaviors. The muscular dystrophy with myositis ( mdm) mouse model is characterized by a deletion in the N2A region of titin. Homozygous mdm mutants are substantially smaller (body mass is ½ to ⅓), have a stiffer gait, and have reduced lifespans compared to their wildtype and heterozygous siblings. In addition, we observed that mutants were heterothermic while wildtypes and heterozygotes were homeothermic when exposed to ambient temperatures ranging from 20-37 °C. We measured the relationship between metabolic rate and the differential between body and ambient temperatures for all three genotypes. As the temperature differential increased, metabolic rates increased more rapidly in the mutants than in wildtype or heterozygous mice, indicating that the mutants have a much higher conductance than their age-matched siblings. We measured shivering frequency in the mdm mice. The frequency of tremor during shivering is expected to be directly proportional to (k/ m)0.5 where k is stiffness and m is body mass. Using an allometric relationship between body mass and shivering frequency, we calculated expected values for all three genotypes based on body mass alone. These predicted values allowed us to take into account the much lower body masses of the mdm mutants. The difference between expected and observed values was significantly larger for mutant mice than wildtypes or heterozygotes. Together, the heterothermy in mutants, the very high conductance, and the decreased tremor frequency demonstrate the thermoregulatory challenges faced by mice with the mdm mutation. Previous work at the whole-muscle level showed that despite the higher passive stiffness observed in mdm mutant muscles, these muscles are more compliant when activated compared to muscles from wildtype mice. The lower tremor frequencies in mutants are consistent with a reduced active muscle stiffness in vivo. These observations suggest that titin affects the tuning of shivering frequency by playing a role in setting active muscle stiffness.