title: Paracrine effects of IGF-1 overexpression on the functional decline due to skeletal muscle disuse: molecular and functional evaluation in hindlimb unloaded MLC/mIgf-1 transgenic mice.
abstract: Slow-twitch muscles, devoted to postural maintenance, experience atrophy and weakness during muscle disuse due to bed-rest, aging or spaceflight. These conditions impair motion activities and can have survival implications. Human and animal studies demonstrate the anabolic role of IGF-1 on skeletal muscle suggesting its interest as a muscle disuse countermeasure. Thus, we tested the role of IGF-1 overexpression on skeletal muscle alteration due to hindlimb unloading (HU) by using MLC/mIgf-1 transgenic mice expressing IGF-1 under the transcriptional control of MLC promoter, selectively activated in skeletal muscle. HU produced atrophy in soleus muscle, in terms of muscle weight and fiber cross-sectional area (CSA) reduction, and up-regulation of atrophy gene MuRF1. In parallel, the disuse-induced slow-to-fast fiber transition was confirmed by an increase of the fast-type of the Myosin Heavy Chain (MHC), a decrease of PGC-1α expression and an increase of histone deacetylase-5 (HDAC5). Consistently, functional parameters such as the resting chloride conductance (gCl) together with ClC-1 chloride channel expression were increased and the contractile parameters were modified in soleus muscle of HU mice. Surprisingly, IGF-1 overexpression in HU mice was unable to counteract the loss of muscle weight and the decrease of fiber CSA. However, the expression of MuRF1 was recovered, suggesting early effects on muscle atrophy. Although the expression of PGC-1α and MHC were not improved in IGF-1-HU mice, the expression of HDAC5 was recovered. Importantly, the HU-induced increase of gCl was fully contrasted in IGF-1 transgenic mice, as well as the changes in contractile parameters. These results indicate that, even if local expression does not seem to attenuate HU-induced atrophy and slow-to-fast phenotype transition, it exerts early molecular effects on gene expression which can counteract the HU-induced modification of electrical and contractile properties. MuRF1 and HDAC5 can be attractive therapeutic targets for pharmacological countermeasures and then deserve further investigations.
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari Aldo Moro, Bari, Italy. sabata.pierno@uniba.it
authors.forename: Sabata
authors.initials: S
authors.lastname: Pierno
authors.forename: Giulia M
authors.initials: GM
authors.lastname: Camerino
authors.forename: Maria
authors.initials: M
authors.lastname: Cannone
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Michela
authors.initials: M
authors.lastname: De Bellis
authors.forename: Claudio
authors.initials: C
authors.lastname: Digennaro
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gramegna
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.forename: Elena
authors.initials: E
authors.lastname: Germinario
authors.forename: Daniela
authors.initials: D
authors.lastname: Danieli-Betto
authors.forename: Romeo
authors.initials: R
authors.lastname: Betto
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dobrowolny
authors.forename: Emanuele
authors.initials: E
authors.lastname: Rizzuto
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001669:Biochemical Phenomena; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000503:physiopathology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008822:Mice, Transgenic; D009119:Muscle Contraction; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000473:pathology / Q000503:physiopathology*; D018994:Myosin Light Chains / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects*; D051381:Rats; D012146:Rest; D016474:Weight-Bearing
chemical_list: D018118:Chloride Channels; D018994:Myosin Light Chains; D007334:Insulin-Like Growth Factor I; D002118:Calcium