title: Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts.
abstract: Myoblasts are mononucleated precursors of myofibers; they persist in mature skeletal muscles for growth and regeneration post injury. During myotonic dystrophy type 1 (DM1), a complex autosomal-dominant neuromuscular disease, the differentiation of skeletal myoblasts into functional myotubes is impaired, resulting in muscle wasting and weakness. The mechanisms leading to this altered differentiation are not fully understood. Here, we demonstrate that the calcium- and voltage-dependent potassium channel, KCa1.1 (BK, Slo1, KCNMA1), regulates myoblast proliferation, migration, and fusion. We also show a loss of plasma membrane expression of the pore-forming α subunit of KCa1.1 in DM1 myoblasts. Inhibiting the function of KCa1.1 in healthy myoblasts induced an increase in cytosolic calcium levels and altered nuclear factor kappa B (NFκB) levels without affecting cell survival. In these normal cells, KCa1.1 block resulted in enhanced proliferation and decreased matrix metalloproteinase secretion, migration, and myotube fusion, phenotypes all observed in DM1 myoblasts and associated with disease pathogenesis. In contrast, introducing functional KCa1.1 α-subunits into DM1 myoblasts normalized their proliferation and rescued expression of the late myogenic marker Mef2. Our results identify KCa1.1 channels as crucial regulators of skeletal myogenesis and suggest these channels as novel therapeutic targets in DM1.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rajeev B
authors.initials: RB
authors.lastname: Tajhya
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xueyou
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Tanner
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Natee
authors.initials: N
authors.lastname: Kongchan
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Neilson
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.|Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Horrigan
authors.affiliation: Department of Pediatrics Neurology, Cincinnati Children's Hospital, Cincinnati, OH 45219, USA.
authors.forename: Lubov T
authors.initials: LT
authors.lastname: Timchenko
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.|Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA.|Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
mesh_terms: D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism*; D009223:Myotonic Dystrophy / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D016328:NF-kappa B; D020778:Matrix Metalloproteinase 2; D002118:Calcium