An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice.
The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that four-and-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress-induced responses important for cardiac hypertrophy. Mice lacking Fhl1 displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the Galphaq (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin- and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.
Sheikh
Farah
F
Department of Medicine, UCSD, La Jolla, California 92093, USA.
Raskin
Anna
A
Chu
Pao-Hsien
PH
Lange
Stephan
S
Domenighetti
Andrea A
AA
Zheng
Ming
M
Liang
Xingqun
X
Zhang
Tong
T
Yajima
Toshitaka
T
Gu
Yusu
Y
Dalton
Nancy D
ND
Mahata
Sushil K
SK
Dorn
Gerald W
GW
Brown
Joan Heller
JH
Heller-Brown
Joan
J
Peterson
Kirk L
KL
Omens
Jeffrey H
JH
McCulloch
Andrew D
AD
Chen
Ju
J
D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D020935:MAP Kinase Signaling System / Q000235:genetics; D040542:Mechanotransduction, Cellular / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics
C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11