title: β-Hydroxy-β-methylbutyrate (HMB) enhances the proliferation of satellite cells in fast muscles of aged rats during recovery from disuse atrophy.
abstract: Loss of myonuclei by apoptosis is thought to contribute to sarcopenia. We have previously shown, that the leucine metabolite, β-hydroxy-β-methylbutyrate (HMB) suppresses apoptotic signaling and the apoptotic index (the ratio of apoptotic positive to apoptotic negative myonuclei) during muscle disuse and during reloading periods after disuse in aged rats. However, it was not clear if the apoptotic signaling indexes were due only to preservation of myonuclei or if perhaps the total myogenic pool increased as a result of HMB-mediated satellite cell proliferation as this would have also reduced the apoptotic index. In this study, we tested the hypothesis that HMB would augment myogenic cells (satellite cells) proliferation during muscle recovery (growth) after a period of disuse in senescent animals. The hindlimb muscles of 34 month old Fisher 344 × Brown Norway rats were unloaded for 14 days by hindlimb suspension (HLS), and then reloaded for 14 days. The rats received either Ca-HMB (340 mg/kg body weight; n = 16), or the vehicle (n = 10) by gavage throughout the experimental period. HMB prevented the functional decline in maximal plantar flexion isometric force production during the reloading period, but not during HLS. HMB-treatment enhanced the proliferation of muscle stem cells as shown by a greater percentage of satellite cells that had proliferated (more BrdU positive, Pax-7 positive, and more Pax7/Ki67 positive nuclei) and as a result, more differentiated stem cells were present (more MyoD/myogenin positive myonuclei), relative to total myonuclei, in reloaded plantaris muscles as compared to reloaded muscles from vehicle-treated animals. Furthermore HMB increased the nuclear protein abundance of proliferation markers, inhibitor of differentiation-2 and cyclin A, as compared to vehicle treatment in reloaded muscles. Although HMB increased phosphorylated Akt during reloading, other mTOR related proteins were not altered by HMB treatment. These data show that HMB improved the proliferation of muscle stem cells in fast twitch plantaris muscles. Enhanced satellite cell proliferation leading to increased differentiated myonuclei should increase the transcriptional potential to support muscle hypertrophic changes and functional changes in sarcopenic muscles, and this could partly explain the reduced apoptotic index in HMB treated muscles. Indeed, muscle mass and fiber cross-sectional area were significantly greater in plantaris muscles from HMB-treated animal muscles after reloading as compared to vehicle-treated animals.
authors.affiliation: Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, WV, USA. salway@hsc.wvu.edu
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Alway
authors.forename: Suzette L
authors.initials: SL
authors.lastname: Pereira
authors.forename: Neile K
authors.initials: NK
authors.lastname: Edens
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Hao
authors.forename: Brian T
authors.initials: BT
authors.lastname: Bennett
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects; D019417:Hindlimb Suspension; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017570:MyoD Protein / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051761:Paired Box Transcription Factors / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014631:Valerates / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D017570:MyoD Protein; C503803:Myog protein, rat; D018008:Myogenin; D009687:Nuclear Proteins; C530821:PAX7 protein, rat; D051761:Paired Box Transcription Factors; D014631:Valerates; C004961:beta-hydroxyisovaleric acid; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: Muscle atrophy; Muscle function; Muscle hypertrophy; Nutrition; Sarcopenia; Satellite cells