title: Autophagic-lysosomal pathway functions in the masseter and tongue muscles in the klotho mouse, a mouse model for aging.
abstract: Klotho mutant (kl/kl) mice, a type of short-lived mouse models, display several aging-related phenotypes. To investigate whether the atrophy of skeletal muscles is induced in these mice via activation of the ubiquitin-proteasomal pathway and/or the autophagic-lysosomal pathway through an alteration of insulin/IGF-I signaling, we analyzed the activity of the two pathways for protein degradation and components of the insulin/IGF signaling pathway in their skeletal muscles. The masseter, tongue, and gastrocnemius muscles in kl/kl showed marked reductions in muscle weight and in myofiber diameter compared with +/+. The autophagic-lysosomal pathway in kl/kl was activated in the masseter and tongue, but not in the gastrocnemius, compared with that in +/+, whereas the ubiquitin-proteasomal pathway in these three muscles of kl/kl was not altered. No marked difference in the phosphorylation levels of insulin/IGF-I signaling components, such as insulin/IGF-I receptor, Akt, and FoxO in three muscles studied were found between kl/kl and +/+, but the phosphorylation levels of signaling component at the downstream of mTOR such as 4E-BP1 and p70 S6K were suppressed in the masseter and tongue of kl/kl compared with +/+. Deficiency of essential amino acids is reported to activate the autophagy-lysosomal pathway through the down-regulation of mTOR, not through IGF-Akt-FoxO. The masseter and tongue seem to be more actively moved than limb muscles in kl/kl, because they are essential for survival activities such as mastication, swallowing, and respiration. Thus, the deficiency of amino acid by the active movement of the masseter and tongue seems to stimulate the autophagic-lysosomal pathway via the down-regulation of mTOR signalling pathway.
authors.affiliation: Department of Geriatic Dentistry, Tsurumi University School of Dental Medicine, Tsurumi-ku, Yokohama, Japan.
authors.forename: Ryo-hei
authors.initials: RH
authors.lastname: Iida
authors.forename: Syuhei
authors.initials: S
authors.lastname: Kanko
authors.forename: Takeo
authors.initials: T
authors.lastname: Suga
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Morito
authors.forename: Akira
authors.initials: A
authors.lastname: Yamane
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000601:Amino Acids, Essential / Q000172:deficiency; D000818:Animals; D001284:Atrophy; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005838:Genotype; D005966:Glucuronidase / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D000090265:Klotho Proteins; D008247:Lysosomes / Q000378:metabolism*; D008406:Masseter Muscle / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014059:Tongue / Q000378:metabolism* / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000601:Amino Acids, Essential; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D051858:Forkhead Transcription Factors; D007328:Insulin; D010750:Phosphoproteins; D025801:Ubiquitin; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; D046988:Proteasome Endopeptidase Complex