The biomechanical environment is an important epigenetic factor. Little is known of how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals and how dysfunction of these pathways may lead to disease. We demonstrate that four and a half LIM domain protein-1 (FHL1) is part of a novel complex within the cardiomyocyte sarcomere, which serves to sense biomechanical stress-induced responses important for cardiac hypertrophy. Fhl1 deficiency in cardiac muscle resulted in a blunted response to hypertrophy and beneficial functional response to pressure overload, induced by transverse aortic constriction. A link to the Galpha-q signaling pathway is shown when Fhl1 deficiency prevents the cardiomyopathy observed in Galpha-q transgenic mice. Mechanistic studies demonstrate that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the stretch sensor domain (titin N2B), which leads to changes in titin and MAPK mediated responses, important for sarcomere extensibility and intracellular signaling. We demonstrate that FHL1 can affect titin N2B expression and mediate changes in muscle compliance that are dependent on titin N2B phosphorylation. We further identify titin N2B as a novel target of ERK2 and demonstrate that a dose-dependent increase in FHL1 interferes with ERK2-mediated titin N2B phosphorylation. These studies identify a novel complex within the cardiomyocyte sarcomere that is critical for biomechanical stress responses in hypertrophy.