FHL1 mutations cause several clinically heterogeneous myopathies including Reducing Body Myopathy (RBM), Scapuloperoneal Myopathy (SPM) and X-Linked Myopathy with Postural Muscle Atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates designated “Reducing Bodies” (RBs) containing mutant FHL1 are detected in RBM muscle but not several other FHL1 myopathies. Here RBM, SPM and XMPMA FHL1 mutants were expressed in C2C12 cells and showed equivalent protein expression to wild-type FHL1 and formed aggregates positive for the RB stain Menadione-NBT, analogous to RBM muscle aggregates. However HCM and EDMD FHL1 mutants generally exhibited reduced expression. Wild-type FHL1 promotes myoblast differentiation however RBM, SPM and XMPMA mutations impaired differentiation, consistent with loss-of-normal function. Furthermore, SPM and XMPMA mutants retarded myotube formation relative to vector control consistent with a dominant-negative/toxic function. Mutant FHL1 myotube formation was partially rescued by expression of the FHL1-binding partner constitutively-active NFATc1. This is the first study to show FHL1 mutations identified in several clinically distinct myopathies lead to similar protein aggregation and impaired myotube formation suggesting a common pathogenic mechanism despite heterogenous clinical features.