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 fourand-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 Gαq (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.

Background: Titin is critical for cardiac muscle function; however, limited knowledge exists of mechanisms important for its regulation. Results: A four-and-a-half LIM domain protein-1/extracellular signal-regulated kinase-2-associated complex modulates titin-N2B levels, phosphorylation, and mechanics. Conclusion: We reveal new mechanisms underlying titin mechano-signaling. Significance: We advance our understanding of how titin-associated complexes/mutations can impact cardiac muscle function and disease.

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Although most studies correlate an increase in systolic stress with pressure overload hypertrophy, there is some evidence suggesting diastolic stress/strain may play the greater role. A culture system was developed in which the application of uniaxial stresses to papillary muscles from knockout (KO) mice can induce a hypertrophic response, while simultaneously assessing tissue mechanical properties. After 5 hrs of 15% stretch, muscles express hypertrophic markers ANP & BNP. By comparing the linear regressions of ANP expression verses passive or active stress we found that a higher statistical correlation exists between ANP induction and passive stress than active systolic stress. We compared the development of hypertrophy in KO mice with abnormal diastolic tissue mechanical properties. ANP gene expression in muscles from muscle LIM protein KO mice, a well characterized mouse model having significant diastolic dysfunction, was ~4 times lower when compared to controls. Four & a half LIM protein (FHL1) KO mice exhibited a blunted hypertrophic response and lower ANP levels after 35 days aortic banding. ANP induction by stretch in muscles from FHL1KO mice was also reduced (P<0.05). FHL1KO muscles exhibited greater diastolic tissue compliance, with no change in systolic mechanics. We conclude that changes in passive mechanics correlate with attenuated development of pressure overload hypertrophy in FHL1KO mice.