Abstract
Four-and-a-half LIM domain protein 1 isoform A (FHL1A) is predominantly expressed in skeletal and cardiac muscle. Mutations in the FHL1 gene are causative for several types of hereditary myopathies including X-linked myopathy with postural muscle atrophy (XMPMA). We here studied myoblasts from XMPMA patients. We found that functional FHL1A protein is completely absent in patient myoblasts. In parallel, expression of FHL1C is either unaffected or increased. Furthermore, a decreased proliferation rate of XMPMA myoblasts compared to controls was observed but an increased number of XMPMA myoblasts was found in the G0/G1 phase. Furthermore, low expression of Kv1.5, a voltage-gated potassium channel known to alter myoblast proliferation during the G1 phase and to control repolarization of action potential, was detected. In order to substantiate a possible relation between Kv1.5 and FHL1C, a pull-down assay was performed. A physical and direct interaction of both proteins was observed in vitro. In addition, confocal microscopy revealed substantial colocalization of FHL1C and Kv1.5 within atrial cells, supporting a possible interaction between both proteins in vivo. Two-electrode voltage clamp experiments demonstrated that coexpression of Kv1.5 with FHL1C in Xenopus laevis oocytes markedly reduced K+ currents when compared to oocytes expressing Kv1.5 only. We here present the first evidence on a biological relevance of FHL1C.
Highlights
LIM, an acronym of three homeodomain-containing transcription factors (Lin-11, Isl-1, and Mec-3), contains a 50–60 amino acid stretch and a highly conserved, double cysteine-rich Zinkfinger domain
A significantly higher number of patient myoblasts was found in the G0/G1 phase when compared to controls
Mutations in Four and a half LIM protein 1 (FHL1) cause distinct types of muscular dystrophies e.g. X-linked myopathy with postural muscle atrophy (XMPMA) [2], which may be associated with cell cycle alterations of myoblasts
Summary
LIM, an acronym of three homeodomain-containing transcription factors (Lin-11, Isl-1, and Mec-3), contains a 50–60 amino acid stretch and a highly conserved, double cysteine-rich Zinkfinger domain. LIM domain-containing proteins play important roles in various cellular processes, such as cytoskeleton organization, signal transduction, gene expression and cell differentiation [1,2]. FHL1 is suggested to play a role in sarcomere synthesis and assembly [3]. Overexpression of FHL1 in mouse skeletal muscle promotes myocardial fusion and hypertrophy, observations with potential implications for human myopathy [4]. FHL1 is predominantly expressed in skeletal muscle and heart, and in other tissues e.g. brain, placenta, lung, liver and kidney, at a lower abundance
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