title: Persistence of regenerative myogenesis in spite of down-regulation of activity-dependent genes in long-term denervated rat muscle.
abstract: Contrary to general expectation, in humans, we have recently shown that after complete conus cauda lesion, the lower motoneuron denervated myofibers may survive several years. In adult rats, the sciatectomized muscle progresses in 4-6 months from severe atrophy to a dystrophic stage and undergoes a dramatic weight loss; during this process, myofiber death/regeneration processes maintain a decreasing population of very small, but vital myofibers. At the same time, in vitro electrophysiologic recordings show that denervated fibers can maintain membrane excitability longer than they can retain contractile properties. A certain level of myofiber regeneration seems to have a role in the process, with the early re-expression of embryonic subunits of integrins and acetylcholine receptor subunits. In the present work, using the reliable real-time quantitative PCR, we confirm the long-lasting occurrence of myoblast proliferation-dependent events and their focal nature. In fact, we show here that in sciatectomized muscle, the expression of 12 selected genes was differentially regulated after 3 and 9 month denervation. At both time points, indexes of muscle activity/inactivity and tissue remodeling (proteolysis, energy usage and angiogenic factors) were down-regulated, while indexes of regenerative myogenesis (Myogenin, MyoD, MRF4 and MHCemb) were up-regulated. Immunohistochemistry with anti-MHCemb and anti-NCAM monoclonal antibodies show that such regeneration events were focally distributed. We conclude that myofiber regeneration is a non-compensatory mechanism, which prolongs the chance of reinnervation during long-lasting denervation. It may also contribute to muscle recovery in paraplegic patients, even when rehabilitation strategies based on functional electric stimulation start late after spinal cord injury (SCI).
authors.affiliation: Department of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Helmut
authors.initials: H
authors.lastname: Kern
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Adami
authors.forename: Donatella
authors.initials: D
authors.lastname: Biral
authors.forename: Sandra
authors.initials: S
authors.lastname: Zampieri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scordari
authors.forename: Simona
authors.initials: S
authors.lastname: di Tullio
authors.forename: Marina
authors.initials: M
authors.lastname: Marini
mesh_terms: D000818:Animals; D002155:Calsequestrin / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009121:Muscle Denervation; D024510:Muscle Development / Q000502:physiology*; D009133:Muscular Atrophy / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002155:Calsequestrin; D019006:Neural Cell Adhesion Molecules; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2