Cardiac-specific Lmpt knockdown induces heart dysfunction via mitochondrial quality decline and metabolic disturbance in Drosophila.

Lmpt (Limpet, CG42679) is a Drosophila LIM domain protein homologous to human FHL2. Our prior work demonstrated it represses Wnt signaling during embryonic cardiac development. However, its role in adult cardiac homeostasis remains unclear. Here, we generated Hand-gal4-driven Lmpt knockdown flies (predominantly targeting adult cardiomyocytes) using the Hand-gal4/UAS-RNAi system and examined its function in adult flies. Lmpt knockdown significantly reduced climbing ability and triggered intrinsic cardiac contractile dysfunction, manifested as bradycardia, impaired fractional shortening and prolonged diastolic intervals in 3-week-old flies. These flies also exhibited systemic metabolic disorders and ATP depletion, decreased lipid accumulation in multiple tissues, and elevated ROS levels in the heart and gut. Meanwhile, Lmpt knockdown led to disorganized and fractured myocardial fibers and progressive age-dependent mitochondrial quality decline. qPCR analysis revealed abnormal expression of genes related to mitochondrial dynamics, respiratory chain, and quality control. In conclusion, Lmpt maintains adult cardiac function by preserving mitochondrial quality, energy metabolism, and myocardial structural integrity. This study provides new insights into the mitochondrial and metabolic mechanisms maintaining adult cardiac homeostasis, with potential implications for FHL2-related cardiomyopathies.