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

Carissa A. Miyano, Santiago F. Orezzoli, C. Loren Buck, Kiisa C Nishikawa

Research output: Contribution to journalArticle

Abstract

Muscular dystrophy with myositis (mdm) mice carry a deletion in the N2A region of the gene for the muscle protein titin (TTN), shiver at low frequency, fail to maintain body temperatures (Tb) at ambient temperatures (Ta) <34°C, and have reduced body mass and active muscle stiffness in vivo compared with 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 the response to cold exposure, we measured Tb and metabolic rate (MR) of WT and mdm mice at four nominal temperatures: 20, 24, 29 and 34°C. Subsequently, we stimulated NST with noradrenaline. 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 with WT mice. NST capacity was lower in mdm mice than in WT mice. Using MR data from a previous study, we compared MR of mdm mice with MR of Perognathus longimembris, a mouse species of similar body mass. Our results indicated low MR and reduced NST of mdm mice. These were more pronounced than differences between mdm and WT mice owing to body mass effects on MR and capacity for NST. Correcting MR using Q10 showed that mdm mice had lower MRs than size-matched P. longimembris, indicating that 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.

Original languageEnglish (US)
JournalThe Journal of experimental biology
Volume222
DOIs
StatePublished - Apr 30 2019

Fingerprint

Connectin
gene deletion
myositis
muscular dystrophy
Myositis
Muscular Dystrophies
Thermogenesis
heat production
gene
mice
Genes
body mass
muscle
Shivering
Temperature
protein
rate
temperature
body temperature
Perognathus

Keywords

  • Body temperature regulation
  • Metabolism
  • Muscular dystrophy with myositis
  • Non-shivering thermogenesis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • Aquatic Science
  • Animal Science and Zoology
  • Molecular Biology
  • Insect Science

Cite this

Severe thermoregulatory deficiencies in mice with a deletion in the titin gene TTN. / Miyano, Carissa A.; Orezzoli, Santiago F.; Buck, C. Loren; Nishikawa, Kiisa C.

In: The Journal of experimental biology, Vol. 222, 30.04.2019.

Research output: Contribution to journalArticle

@article{bc7768fedc4648208173119ec63cdc2a,
title = "Severe thermoregulatory deficiencies in mice with a deletion in the titin gene TTN",
abstract = "Muscular dystrophy with myositis (mdm) mice carry a deletion in the N2A region of the gene for the muscle protein titin (TTN), shiver at low frequency, fail to maintain body temperatures (Tb) at ambient temperatures (Ta) <34°C, and have reduced body mass and active muscle stiffness in vivo compared with 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 the response to cold exposure, we measured Tb and metabolic rate (MR) of WT and mdm mice at four nominal temperatures: 20, 24, 29 and 34°C. Subsequently, we stimulated NST with noradrenaline. 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 with WT mice. NST capacity was lower in mdm mice than in WT mice. Using MR data from a previous study, we compared MR of mdm mice with MR of Perognathus longimembris, a mouse species of similar body mass. Our results indicated low MR and reduced NST of mdm mice. These were more pronounced than differences between mdm and WT mice owing to body mass effects on MR and capacity for NST. Correcting MR using Q10 showed that mdm mice had lower MRs than size-matched P. longimembris, indicating that 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.",
keywords = "Body temperature regulation, Metabolism, Muscular dystrophy with myositis, Non-shivering thermogenesis",
author = "Miyano, {Carissa A.} and Orezzoli, {Santiago F.} and Buck, {C. Loren} and Nishikawa, {Kiisa C}",
year = "2019",
month = "4",
day = "30",
doi = "10.1242/jeb.198564",
language = "English (US)",
volume = "222",
journal = "Journal of Experimental Biology",
issn = "0022-0949",
publisher = "Company of Biologists Ltd",

}

TY - JOUR

T1 - Severe thermoregulatory deficiencies in mice with a deletion in the titin gene TTN

AU - Miyano, Carissa A.

AU - Orezzoli, Santiago F.

AU - Buck, C. Loren

AU - Nishikawa, Kiisa C

PY - 2019/4/30

Y1 - 2019/4/30

N2 - Muscular dystrophy with myositis (mdm) mice carry a deletion in the N2A region of the gene for the muscle protein titin (TTN), shiver at low frequency, fail to maintain body temperatures (Tb) at ambient temperatures (Ta) <34°C, and have reduced body mass and active muscle stiffness in vivo compared with 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 the response to cold exposure, we measured Tb and metabolic rate (MR) of WT and mdm mice at four nominal temperatures: 20, 24, 29 and 34°C. Subsequently, we stimulated NST with noradrenaline. 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 with WT mice. NST capacity was lower in mdm mice than in WT mice. Using MR data from a previous study, we compared MR of mdm mice with MR of Perognathus longimembris, a mouse species of similar body mass. Our results indicated low MR and reduced NST of mdm mice. These were more pronounced than differences between mdm and WT mice owing to body mass effects on MR and capacity for NST. Correcting MR using Q10 showed that mdm mice had lower MRs than size-matched P. longimembris, indicating that 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.

AB - Muscular dystrophy with myositis (mdm) mice carry a deletion in the N2A region of the gene for the muscle protein titin (TTN), shiver at low frequency, fail to maintain body temperatures (Tb) at ambient temperatures (Ta) <34°C, and have reduced body mass and active muscle stiffness in vivo compared with 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 the response to cold exposure, we measured Tb and metabolic rate (MR) of WT and mdm mice at four nominal temperatures: 20, 24, 29 and 34°C. Subsequently, we stimulated NST with noradrenaline. 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 with WT mice. NST capacity was lower in mdm mice than in WT mice. Using MR data from a previous study, we compared MR of mdm mice with MR of Perognathus longimembris, a mouse species of similar body mass. Our results indicated low MR and reduced NST of mdm mice. These were more pronounced than differences between mdm and WT mice owing to body mass effects on MR and capacity for NST. Correcting MR using Q10 showed that mdm mice had lower MRs than size-matched P. longimembris, indicating that 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.

KW - Body temperature regulation

KW - Metabolism

KW - Muscular dystrophy with myositis

KW - Non-shivering thermogenesis

UR - http://www.scopus.com/inward/record.url?scp=85065510440&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065510440&partnerID=8YFLogxK

U2 - 10.1242/jeb.198564

DO - 10.1242/jeb.198564

M3 - Article

VL - 222

JO - Journal of Experimental Biology

JF - Journal of Experimental Biology

SN - 0022-0949

ER -