Humanin detected in skeletal muscles of MELAS patients: a possible new therapeutic agent.
Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis induced by various types of Alzheimer's disease-related insults. We have previously indicated that HN increases cellular ATP levels and speculated that this peptide may rescue energy-deficient cells in mitochondrial disorders. Here, we report, for the first time, increased HN expression in skeletal muscles from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). HN was strongly positive in all ragged-red fibers (RRFs) and some non-RRFs, and most of them were type 1 fibers generally requiring higher energy than type 2 fibers. HN in these fibers was localized in mitochondria. HN expression was also increased in small arteries that strongly reacted for succinate dehydrogenase. Our experiments on muscular TE671 cells indicated the possibility that synthesized HN increases cellular ATP levels by directly acting on mitochondria. From these in vivo and in vitro findings, we propose that HN expression might be induced in response to the energy crisis within affected fibers and vessels in MELAS muscles and further be a possible therapeutic candidate for MELAS.
Kariya
Shingo
S
Department of Neurology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522 Nara, Japan.
Hirano
Makito
M
Furiya
Yoshiko
Y
Sugie
Kazuma
K
Ueno
Satoshi
S
D000251:Adenosine Triphosphatases / Q000378:metabolism; D045744:Cell Line, Tumor; D018834:Chaperonin 60 / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017241:MELAS Syndrome / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012208:Rhabdomyosarcoma; D013385:Succinate Dehydrogenase / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D018834:Chaperonin 60; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C427211:humanin; C007293:DAPI; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases