title: Molecular signatures of age-associated chronic degeneration of shoulder muscles.
abstract: Chronic muscle diseases are highly prevalent in the elderly causing severe mobility limitations, pain and frailty. The intrinsic molecular mechanisms are poorly understood due to multifactorial causes, slow progression with age and variations between individuals. Understanding the underlying molecular mechanisms could lead to new treatment options which are currently limited. Shoulder complaints are highly common in the elderly, and therefore, muscles of the shoulder's rotator cuff could be considered as a model for chronic age-associated muscle degeneration. Diseased shoulder muscles were characterized by muscle atrophy and fatty infiltration compared with unaffected shoulder muscles. We confirmed fatty infiltration using histochemical analysis. Additionally, fibrosis and loss of contractile myosin expression were found in diseased muscles. Most cellular features, including proliferation rate, apoptosis and cell senescence, remained unchanged and genome-wide molecular signatures were predominantly similar between diseased and intact muscles. However, we found down-regulation of a small subset of muscle function genes, and up-regulation of extracellular region genes. Myogenesis was defected in muscle cell culture from diseased muscles but was restored by elevating MyoD levels. We suggest that impaired muscle functionality in a specific environment of thickened extra-cellular matrix is crucial for the development of chronic age-associated muscle degeneration.
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Raz
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan Ferdinand
authors.initials: JF
authors.lastname: Henseler
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Kolk
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Zuotian
authors.initials: Z
authors.lastname: Tatum
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Niels Kuipers
authors.initials: NK
authors.lastname: Groosjohan
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nisha E
authors.initials: NE
authors.lastname: Verwey
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wibowo
authors.initials: W
authors.lastname: Arindrarto
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Szymon M
authors.initials: SM
authors.lastname: Kielbasa
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jochem
authors.initials: J
authors.lastname: Nagels
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rob G H H
authors.initials: RG
authors.lastname: Nelissen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000375:Aging / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017006:Rotator Cuff / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D012782:Shoulder / Q000473:pathology* / Q000601:surgery
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger
keywords: Gerotarget; atrophy; deep RNA-seq; fatty infiltration; muscle satellite cells; shoulder disease