TY - JOUR
T1 - Optimal length, calcium sensitivity and twitch characteristics of skeletal muscles from mdm mice with a deletion in N2A titin
AU - Hessel, Anthony L.
AU - Joumaa, Venus
AU - Eck, Sydney
AU - Herzog, Walter
AU - Nishikawa, Kiisa C.
N1 - Funding Information:
This work was supported by the National Science Foundation [IOS-0732949, IOS-1025806 and IOS-1456868 to K.C.N.], the W. M. Keck Foundation [K.C.N.], and the Achievement Rewards for College Scientists Foundation [A.L.H.].
Publisher Copyright:
© 2019. Published by The Company of Biologists Ltd
PY - 2019
Y1 - 2019
N2 - During isometric contractions, the optimal length of skeletal muscles increases with decreasing activation. The underlying mechanism for this phenomenon is thought to be linked to length dependence of Ca2+ sensitivity. Muscular dystrophy with myositis (mdm), a recessive titin mutation in mice, was used as a tool to study the role of titin in activation dependence of optimal length and length dependence of Ca2+ sensitivity. We measured the shift in optimal length between tetanic and twitch stimulation in mdm and wild-type muscles, and the length dependence of Ca2+ sensitivity at short and long sarcomere lengths in mdm and wild-type fiber bundles. The results indicate that the mdm mutation leads to a loss of activation dependence of optimal length without the expected change in length dependence of Ca2+ sensitivity, demonstrating that these properties are not linked, as previously suggested. Furthermore, mdm muscles produced maximum tetanic stress during sub-optimal filament overlap at lengths similar to twitch contractions in both genotypes, but the difference explains less than half of the observed reduction in active force of mdm muscles. Mdm muscles also exhibited increased electromechanical delay, contraction and relaxation times, and decreased rate of force development in twitch contractions. We conclude that the small deletion in titin associated with mdm in skeletal muscles alters force production, suggesting an important regulatory role for titin in active force production. The molecular mechanisms for titin’s role in regulating muscle force production remain to be elucidated.
AB - During isometric contractions, the optimal length of skeletal muscles increases with decreasing activation. The underlying mechanism for this phenomenon is thought to be linked to length dependence of Ca2+ sensitivity. Muscular dystrophy with myositis (mdm), a recessive titin mutation in mice, was used as a tool to study the role of titin in activation dependence of optimal length and length dependence of Ca2+ sensitivity. We measured the shift in optimal length between tetanic and twitch stimulation in mdm and wild-type muscles, and the length dependence of Ca2+ sensitivity at short and long sarcomere lengths in mdm and wild-type fiber bundles. The results indicate that the mdm mutation leads to a loss of activation dependence of optimal length without the expected change in length dependence of Ca2+ sensitivity, demonstrating that these properties are not linked, as previously suggested. Furthermore, mdm muscles produced maximum tetanic stress during sub-optimal filament overlap at lengths similar to twitch contractions in both genotypes, but the difference explains less than half of the observed reduction in active force of mdm muscles. Mdm muscles also exhibited increased electromechanical delay, contraction and relaxation times, and decreased rate of force development in twitch contractions. We conclude that the small deletion in titin associated with mdm in skeletal muscles alters force production, suggesting an important regulatory role for titin in active force production. The molecular mechanisms for titin’s role in regulating muscle force production remain to be elucidated.
KW - Activation-dependent properties
KW - Connectin
KW - Force transmission
KW - Isometric force production
KW - Length-dependent properties
KW - Muscular dystrophy with myositis
KW - Submaximal force production
UR - http://www.scopus.com/inward/record.url?scp=85068429040&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068429040&partnerID=8YFLogxK
U2 - 10.1242/jeb.200840
DO - 10.1242/jeb.200840
M3 - Article
C2 - 31097600
AN - SCOPUS:85068429040
SN - 0022-0949
VL - 222
JO - Journal of Experimental Biology
JF - Journal of Experimental Biology
IS - 12
M1 - jeb200840
ER -