Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice
نویسندگان
چکیده
BACKGROUND 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. OBJECTIVE The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly. MATERIAL AND METHODS 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. RESULTS 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. CONCLUSIONS 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.
منابع مشابه
Expression of uncoupling protein 1 in skeletal muscle decreases muscle energy efficiency and affects thermoregulation and substrate oxidation.
Skeletal muscle uncoupling by ectopic expression of mitochondrial uncoupling protein 1 (UCP1) has been shown to result in a lean phenotype in mice characterized by increased energy expenditure (EE), resistance to diet-induced obesity, and improved glucose tolerance. Here, we investigated in detail the effect of ectopic UCP1 expression in skeletal muscle on thermoregulation and energy homeostasi...
متن کاملMicroarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy
BACKGROUND Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ A...
متن کاملOverexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy.
This study examined the association between local insulin-like growth factor I (IGF-I) overexpression and atrophy in skeletal muscle. We hypothesized that endogenous skeletal muscle IGF-I mRNA expression would decrease with hindlimb unloading (HU) in mice, and that transgenic mice overexpressing human IGF-I (hIGF-I) specifically in skeletal muscle would exhibit less atrophy after HU. Male trans...
متن کاملRole of AP-1/RE-1 Binding Site in Transcriptional Regulation of MMP-2 in Skeletal Muscle Atrophy
INTRODUCTION: Increased expression of matrix metalloproteinase-2 (MMP-2) has been reported in various skeletal muscle atrophy models. In our previous work, we have shown significantly increased MMP-2 expression in a mouse Achilles tendon transection model [1]. However, the mechanism of transcriptional regulation of MMP-2 in skeletal muscle atrophy remains largely uninvestigated. Recently work s...
متن کاملInsulin-like growth factor I slows the rate of denervation induced skeletal muscle atrophy.
Loss of the nerve supply to skeletal muscle results in a relentless loss of muscle mass (atrophy) over time. The ability of insulin-like growth factor-1 to reduce atrophy resulting from denervation was examined after transection of the sciatic nerve in transgenic MLC/mIGF-1 mice that over-express mIGF-1 specifically in differentiated myofibres. The cross sectional area (CSA) of all types of myo...
متن کامل