title: Improvement of Physical Decline Through Combined Effects of Muscle Enhancement and Mitochondrial Activation by a Gastric Hormone Ghrelin in Male 5/6Nx CKD Model Mice.
abstract: Because a physical decline correlates with an increased risk of a wide range of disease and morbidity, an improvement of physical performance is expected to bring significant clinical benefits. The primary cause of physical decline in 5/6 nephrectomized (5/6Nx) chronic kidney disease model mice has been regarded as a decrease in muscle mass; however, our recent study showed that a decrease in muscle mitochondria plays a critical role. In the present study, we examined the effects of a gastric hormone ghrelin, which has been reported to promote muscle mitochondrial oxidation, on the physical decline in the chronic kidney disease model mice, focusing on the epigenetic modulations of a mitochondrial activator gene, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Ghrelin treatment improved a decline in exercise endurance of 5/6Nx mice, associated with an increase in both of the muscle mass and mitochondrial amount. The expression level of PGC-1α was decreased in the skeletal muscle of 5/6Nx mice, which was associated with an increase in the methylation ratio of the cytosine residue at 260 base pairs upstream of the initiation point. Conversely, ghrelin treatment de-methylated the cytosine residue and increased the expression of PGC-1α. A representative muscle anabolic factor, IGF-1, did not affect the expression of PGC-1α and muscle mitochondrial amount, although it increased muscle mass. As a result, IGF-1 treatment in 5/6Nx mice did not increase the decreased exercise endurance as effectively as ghrelin treatment did. These findings indicate an advantage of ghrelin treatment for a recovery of physical decline.
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tamaki
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Hagiwara
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Miyashita
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Fujii
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Mitsuishi
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Muraki
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Internal Medicine (M.T., A.H., K.M., S.W., H.In., K.F., C.F., M.S., M.M., A.M., K.H., H.It.), School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; and Department of Nephrology (M.T., T.D.), Tokushima University Hospital, Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D018908:Muscle Weakness / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009392:Nephrectomy; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D054439:Ghrelin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D054440:Receptors, Ghrelin; D014157:Transcription Factors; D003576:Electron Transport Complex IV; D055372:AMP-Activated Protein Kinases