title: β-Hydroxy β-methylbutyrate improves dexamethasone-induced muscle atrophy by modulating the muscle degradation pathway in SD rat.
abstract: Skeletal muscle atrophy results from various conditions including high levels of glucocorticoids, and β-hydroxy β-methylbutyrate (HMB; a metabolite of leucine) is a potent therapeutical supplement used to treat various muscle disorders. Recent studies have demonstrated that HMB inhibits dexamethasone-induced atrophy in cultured myotubes, but its effect on dexamethasone-induced muscle atrophy has not been determined in vivo. In the present study, we investigated the effect of HMB on dexamethasone-induced muscle atrophy in rats. Treatment with dexamethasone weakened grip strengths and increased muscle damage as determined by increased serum creatine kinase levels and by histological analysis. Dexamethasone treatment also reduced both soleus and gastrocnemius muscle masses. However, HMB supplementation significantly prevented reductions in grip strengths, reduced muscle damage, and prevented muscle mass and protein concentration decrease in soleus muscle. Biochemical analysis demonstrated that dexamethasone markedly increased levels of MuRF1 protein, which causes the ubiquitination and degradation of MyHC. Indeed, dexamethasone treatment decreased MyHC protein expression and increased the ubiquitinated-MyHC to MyHC ratio. However, HMB supplementation caused the down-regulations of MuRF1 protein and of ubiquitinated-MyHC. Furthermore, additional experiments provided evidence that HMB supplementation inhibited the nuclear translocation of FOXO1 induced by dexamethasone, and showed increased MyoD expression in the nuclear fractions of soleus muscles. These findings suggest that HMB supplementation attenuates dexamethasone-induced muscle wasting by regulating FOXO1 transcription factor and subsequent MuRF1 expression. Accordingly, our results suggest that HMB supplementation could be used to prevent steroid myopathy.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Kyung Kyun
authors.initials: KK
authors.lastname: Noh
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Min Hi
authors.initials: MH
authors.lastname: Park
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Jang
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Chan Hum
authors.initials: CH
authors.lastname: Park
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Changshin
authors.initials: C
authors.lastname: Yoon
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Longevity Life Science and Technology Institute, Pusan National University, Busan, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D003907:Dexamethasone / Q000009:adverse effects*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D018737:Hand Strength / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D009133:Muscular Atrophy / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014631:Valerates / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1
chemical_list: D003402:Creatine Kinase; D003907:Dexamethasone; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D014631:Valerates; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C004961:beta-hydroxyisovaleric acid; C499086:Trim63 protein, rat