title: Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength.
abstract: Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolismin vitroandin vivoWe found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Summermatter
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Anais
authors.initials: A
authors.lastname: Bouzan
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Eliane
authors.initials: E
authors.lastname: Pierrel
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Melly
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stauffer
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gutzwiller
authors.affiliation: Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Nolin
authors.affiliation: Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Dornelas
authors.affiliation: Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Christy
authors.initials: C
authors.lastname: Fryer
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Juliet
authors.initials: J
authors.lastname: Leighton-Davies
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland brigitte.fournier@novartis.com.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fournier
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D048429:Cell Size; D020868:Gene Silencing; D005938:Glucocorticoids / Q000009:adverse effects; D006801:Humans; D006984:Hypertrophy; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D053580:Muscle Strength / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy; D009929:Organ Size; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D055948:Sarcopenia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation; D015032:Zinc / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; C491053:MT2A protein, human; C491054:Mt2 protein, mouse; C407523:metallothionein isoform 1; D008668:Metallothionein; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D015032:Zinc
keywords: muscle metabolism