title: Morphological and molecular aspects of immobilization-induced muscle atrophy in rats at different stages of postnatal development: the role of autophagy.
abstract: Muscle loss occurs following injury and immobilization in adulthood and childhood, which impairs the rehabilitation process; however, far fewer studies have been conducted analyzing atrophic response in infants. This work investigated first the morphological and molecular mechanisms involved in immobilization-induced atrophy in soleus muscles from rats at different stages of postnatal development [i.e., weanling (WR) and adult (AR) rats] and, second, the role of autophagy in regulating muscle plasticity during immobilization. Hindlimb immobilization for 10 days reduced muscle mass and fiber cross-sectional area, with more pronounced atrophy in WR, and induced slow-to-fast fiber switching. These effects were accompanied by a decrease in markers of protein synthesis and an increase in autophagy. The ubiquitin (Ub)-ligase MuRF1 and the ubiquitinated proteins were upregulated by immobilization in AR while the autolyzed form of μ-calpain was increased in WR. To further explore the role of autophagy in muscle abnormalities, AR were concomitantly immobilized and treated with colchicine, which blocks autophagosome-lysosome fusion. Colchicine-treated immobilized muscles had exacerbated atrophy and presented degenerative features. Despite Igf1/Akt signaling was downregulated in immobilized muscles from both age groups, Foxo1 and 4 phosphorylation was increased in WR. In the same group of animals, Foxo1 acetylation and Foxo1 and 4 content was increased and decreased, respectively. Our data show that muscle disorders induced by 10-day-immobilization occur in both age-dependent and -independent manners, an understanding that may optimize treatment outcomes in infants. We also provide further evidence that the strong inhibition of autophagy may be ineffective for treating muscle atrophy.
authors.affiliation: Department of Biomechanics, Medicine, and Rehabilitation of the Locomotor Apparatus, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil;
authors.forename: Camila Silva
authors.initials: CS
authors.lastname: Foresto
authors.affiliation: Department of Biochemistry/Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Paula-Gomes
authors.affiliation: Department of Physiology Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Wilian Assis
authors.initials: WA
authors.lastname: Silveira
authors.affiliation: Department of Physiology Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Flávia Aparecida
authors.initials: FA
authors.lastname: Graça
authors.affiliation: Department of Physiology Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; and Department of Biochemistry/Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Isis do Carmo
authors.initials: Ido C
authors.lastname: Kettelhut
authors.affiliation: Department of Physiology Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; and Department of Biochemistry/Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil dawitapg@rfi.fmrp.usp.br.
authors.forename: Dawit Albieiro Pinheiro
authors.identifier: 0000-0003-2621-3330
authors.initials: DA
authors.lastname: Gonçalves
authors.affiliation: Department of Biomechanics, Medicine, and Rehabilitation of the Locomotor Apparatus, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil;
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Mattiello-Sverzut
mesh_terms: D000222:Adaptation, Physiological; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D005260:Female; D019417:Hindlimb Suspension; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar
keywords: Igf1/Akt/Foxo signaling; autophagy; fiber type; muscle atrophy; protein metabolism