Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice

Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in fourand- a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing bodymyopathy and Emery-Dreifuss muscular dystrophy. However, itremains tobe clarifiedwhethermutationsinFHL1 cause skeletalmuscleremodelingowingto gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-offunction effects on skeletalmuscle homeostasis. Histological and functional analyses of soleus, tibialis anterior andsternohyoideusmusclesdemonstratedthatFHL1-nullmicedevelopanage-dependentmyopathyassociated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates inFHL1-nullmice,associatedwithage-dependentimpairmentofmusclecontractile functionanda significantly lower exercise capacity.Analysis of primarymyoblasts isolated fromFHL1-nullmusclesdemonstrated early muscle fiber differentiation and maturation defects,which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations.