Severe thermoregulatory deficiencies in mice with a deletion in the titin gene

Muscular dystrophy with myositis (mdm) mice carry a deletion in the N2A region of the gene for the muscle protein titin, shiver at low frequency, fail to maintain body temperatures (Tb) at ambient temperatures (Ta) <34 °C, and have reduced body mass (BM) and active muscle stiffness in vivo compared to wild type (WT) siblings. Impaired shivering thermogenesis (ST) could be due to the mutated titin protein causing more compliant muscles. We hypothesized that non shivering thermogenesis (NST) is impaired. To characterize response to cold exposure, we measured Tb and metabolic rate (MR) of WT and mdm mice at four nominal temperatures: 20 °C, 24 °C, 29 °C, and 34 °C. Subsequently, we stimulated NST with norepinephrine. Manipulation of Ta revealed an interaction between genotype and MR; mdm mice had higher MRs at 29 °C and lower MRs at 24 °C compared to WT. NST capacity was lower in mdm mice than in WT. Using MRs from a previous study, we compared MR of mdm mice to Perognathus longimembris, a mouse species of similar BM. Our results indicated low MR and reduced NST of mdm mice. These were more pronounced than differences between mdm and WT mice due to BM effects on MR and capacity for NST. Correcting MR using Q10 showed that mdm mice had lower MRs than size-matched P. longimembris, indicating mutated N2A titin causes severe thermoregulatory defects at all levels. Direct effects of the titin mutation lead to lower shivering frequency. Indirect effects likely lead to a lower capacity for NST and increased thermal conductance through decreased body size.