tacrolimus and Muscular-Atrophy

Optogenetic technologies have been the subject of great excitement within the scientific community for their ability to demystify complex neurophysiological pathways in the central (CNS) and peripheral nervous systems (PNS). The excitement surrounding optogenetics has also extended to the clinic with a trial for ChR2 in the treatment of retinitis pigmentosa currently underway and additional trials anticipated for the near future. In this work, we identify the cause of loss-of-expression in response to transdermal illumination of an optogenetically active peroneal nerve following an anterior compartment (AC) injection of AAV6-hSyn-ChR2(H134R) with and without a fluorescent reporter. Using Sprague Dawley Rag2

Topics: Animals; Cell Survival; Channelrhodopsins; Dependovirus; DNA-Binding Proteins; Genetic Vectors; Motor Neurons; Muscular Atrophy; Nuclear Proteins; Optogenetics; Peroneal Nerve; Rats; Rats, Sprague-Dawley; Spinal Cord; Synapsins; Tacrolimus

Formation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly.. The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly.. A ligand-activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle α-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice.. HSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2α in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice.. As a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics.

Topics: Actins; Amino Acids; Animals; Disease Models, Animal; eIF-2 Kinase; Homeostasis; Humans; Intracellular Space; Ligands; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Mice, Transgenic; Multiprotein Complexes; Muscle, Skeletal; Muscular Atrophy; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Tacrolimus; TOR Serine-Threonine Kinases

Calcineurin (CaN) signaling pathway has been implicated in the transcriptional regulation of slow muscle fiber genes and in muscle hypertrophy. Our aim was to investigate the functional role of CaN as a regulator of muscle growth and/or muscle fiber type under conditions of recovery from inactivity.. Female ICR mice (8 wk of age, 28-32 g) were used. To examine the effects of hindlimb suspension (HS) and reloading on skeletal muscle fiber size and muscle fiber type, animals were designated to 8 wk of HS and subsequent reloading for 4 wk. During reloading, animals were treated with pharmacological inhibitors for CaN (FK506) by intraperitoneal administration (3-5 mg.kg.d). After each experimental period, antigravitational soleus muscle was analyzed.. HS treatment resulted in obvious muscle atrophy and slow-to-fast fiber-type transformation in the soleus muscle. Subsequent reloading for 4 wk following HS induced muscle regrowth and fiber-type reversion toward a slow profile. FK506 administration prevented this kind of reloading-induced transformation of muscle fiber type. Furthermore, it was confirmed that FK506 administration attenuated maintenance of fiber cross-sectional area and reloading-induced fiber regrowth, specifically in slow-type muscle fibers.. Reloading-induced fiber-type reversion toward a slow profile is prevented by the pharmacological inhibition of CaN. Additionally, inhibition of CaN prevented maintenance and regrowth of slow-type muscle fibers. These results implicate that the CaN signaling pathway is required in the slow-type muscle fiber program under maintenance and suspension-reloading conditions.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Female; Hindlimb Suspension; Immunosuppressive Agents; Mice; Mice, Inbred ICR; Muscle Development; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Muscular Atrophy; Myosin Heavy Chains; Protein Isoforms; Recovery of Function; Signal Transduction; Tacrolimus; Weight-Bearing