Abstract
Muscle wasting and atrophy are regulated by multiple molecular processes, including mRNA processing. Reduced levels of the polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, cause muscle atrophy. A proteomic study in muscles with reduced PABPN1 levels suggested dysregulation of sarcomeric and cytoskeletal proteins. Here we investigated the hypothesis that reduced PABPN1 levels lead to an aberrant organization of the cytoskeleton. MURC, a plasma membrane-associated protein, was found to be more abundant in muscles with reduced PABPN1 levels, and it was found to be expressed at regions showing regeneration. A polarized cytoskeletal organization is typical for muscle cells, but muscle cells with reduced PABPN1 levels (named as shPAB) were characterized by a disorganized cytoskeleton that lacked polarization. Moreover, cell mechanical features and myogenic differentiation were significantly reduced in shPAB cells. Importantly, restoring cytoskeletal stability, by actin overexpression, was beneficial for myogenesis, expression of sarcomeric proteins and proper localization of MURC in shPAB cell cultures and in shPAB muscle bundle. We suggest that poor cytoskeletal mechanical features are caused by altered expression levels of cytoskeletal proteins and contribute to muscle wasting and atrophy.
Highlights
Muscle wasting and atrophy are regulated by multiple molecular processes, including mRNA processing
Abbreviations polyadenylation binding protein nucleus 1 (PABPN1) Polyadenylation binding protein nucleus 1 oculopharyngeal muscular dystrophy (OPMD) Oculopharyngeal muscular dystrophy Named shPab in mouse and shPAB in human Reduced PABPN1 levels alternative polyadenylation site (APA) Alternative polyadenylation site Myosin heavy chain isoforms (MyHC) Myosin heavy chain DMD Duchenne muscular dystrophy
An expansion mutation in PABPN1 is the genetic cause for oculopharyngeal muscular dystrophy (OPMD), a late onset myopathy that is characterized by muscle wasting
Summary
Muscle wasting and atrophy are regulated by multiple molecular processes, including mRNA processing. Reduced levels of the polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, cause muscle atrophy. A polarized cytoskeletal organization is typical for muscle cells, but muscle cells with reduced PABPN1 levels (named as shPAB) were characterized by a disorganized cytoskeleton that lacked polarization. We suggest that poor cytoskeletal mechanical features are caused by altered expression levels of cytoskeletal proteins and contribute to muscle wasting and atrophy. Abbreviations PABPN1 Polyadenylation binding protein nucleus 1 OPMD Oculopharyngeal muscular dystrophy Named shPab in mouse and shPAB in human Reduced PABPN1 levels APA Alternative polyadenylation site MyHC Myosin heavy chain DMD Duchenne muscular dystrophy. Others and we showed that reduced levels of polyadenylation binding protein 1 (PABPN1) cause muscle wasting, including muscle atrophy, extracellular matrix thickening, myofiber typing transitions and central n ucleation[6,7]. Those conditions can be modeled by the expression of shRNA to PABPN1, leading to reduced PABPN1 levels (named shPab in mouse and shPAB in human)[5,6]
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