PMID- 30110564 OWN - NLM STAT- MEDLINE DCOM- 20190703 LR - 20211204 IS - 1522-1563 (Electronic) IS - 0363-6143 (Print) IS - 0363-6143 (Linking) VI - 315 IP - 5 DP - 2018 Nov 1 TI - Hydrogen sulfide alleviates hyperhomocysteinemia-mediated skeletal muscle atrophy via mitigation of oxidative and endoplasmic reticulum stress injury. PG - C609-C622 LID - 10.1152/ajpcell.00147.2018 [doi] AB - Although hyperhomocysteinemia (HHcy) occurs because of the deficiency in cystathionine-beta-synthase (CBS) causing skeletal muscle dysfunction, it is still unclear whether this effect is mediated through oxidative stress, endoplasmic reticulum (ER) stress, or both. Nevertheless, there is no treatment option available to improve HHcy-mediated muscle injury. Hydrogen sulfide (H(2)S) is an antioxidant compound, and patients with CBS mutation do not produce H(2)S. In this study, we hypothesized that H(2)S mitigates HHcy-induced redox imbalance/ER stress during skeletal muscle atrophy via JNK phosphorylation. We used CBS(+/-) mice to study HHcy-mediated muscle atrophy, and treated them with sodium hydrogen sulfide (NaHS; an H(2)S donor). Proteins and mRNAs were examined by Western blots and quantitative PCR. Proinflammatory cytokines were also measured. Muscle mass and strength were studied via fatigue susceptibility test. Our data revealed that HHcy was detrimental to skeletal mass, particularly gastrocnemius and quadriceps muscle weight. We noticed that oxidative stress was reversed by NaHS in homocysteine (Hcy)-treated C2C12 cells. Interestingly, ER stress markers (GRP78, ATF6, pIRE1alpha, and pJNK) were elevated in vivo and in vitro, and NaHS mitigated these effects. Additionally, we observed that JNK phosphorylation was upregulated in C2C12 after Hcy treatment, but NaHS could not reduce this effect. Furthermore, inflammatory cytokines IL-6 and TNF-alpha were higher in plasma from CBS as compared with wild-type mice. FOXO1-mediated Atrogin-1 and MuRF-1 upregulation were attenuated by NaHS. Functional studies revealed that NaHS administration improved muscle fatigability in CBS(+/-) mice. In conclusion, our work provides evidence that NaHS is beneficial in mitigating HHcy-mediated skeletal injury incited by oxidative/ER stress responses. FAU - Majumder, Avisek AU - Majumder A AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. AD - Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine , Louisville, Kentucky. FAU - Singh, Mahavir AU - Singh M AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. FAU - Behera, Jyotirmaya AU - Behera J AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. FAU - Theilen, Nicholas T AU - Theilen NT AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. FAU - George, Akash K AU - George AK AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. FAU - Tyagi, Neetu AU - Tyagi N AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. FAU - Metreveli, Naira AU - Metreveli N AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. FAU - Tyagi, Suresh C AU - Tyagi SC AD - Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20180815 PL - United States TA - Am J Physiol Cell Physiol JT - American journal of physiology. Cell physiology JID - 100901225 RN - 0 (Activating Transcription Factor 6) RN - 0 (Antioxidants) RN - 0 (Atf6 protein, mouse) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Forkhead Box Protein O1) RN - 0 (Foxo1 protein, mouse) RN - 0 (HSPA5 protein, human) RN - 0 (Heat-Shock Proteins) RN - 0 (Hspa5 protein, mouse) RN - 0 (Interleukin-6) RN - 0 (Muscle Proteins) RN - 0 (Sulfites) RN - 0 (Tripartite Motif Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 91829-63-9 (sodium hydrogen sulfite) RN - EC 2.3.2.27 (Fbxo32 protein, mouse) RN - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases) RN - EC 2.3.2.27 (Trim63 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.11.1 (Ern1 protein, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 4) RN - EC 3.1.- (Endoribonucleases) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) SB - IM MH - Activating Transcription Factor 6/genetics MH - Animals MH - Antioxidants/administration & dosage MH - Cystathionine beta-Synthase/*genetics MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/drug effects MH - Endoribonucleases/genetics MH - Forkhead Box Protein O1/genetics MH - Gene Expression Regulation/drug effects MH - Heat-Shock Proteins/genetics MH - Humans MH - Hyperhomocysteinemia/blood/complications/*drug therapy/genetics MH - Interleukin-6/blood MH - MAP Kinase Kinase 4/genetics MH - Mice MH - Muscle Proteins/genetics MH - Muscle Strength/drug effects MH - Muscle, Skeletal/drug effects/pathology MH - Muscular Atrophy/blood/*drug therapy/etiology/genetics MH - Oxidative Stress/drug effects MH - Protein Serine-Threonine Kinases/genetics MH - SKP Cullin F-Box Protein Ligases/genetics MH - Sulfites/*administration & dosage MH - Tripartite Motif Proteins/genetics MH - Tumor Necrosis Factor-alpha/blood MH - Ubiquitin-Protein Ligases/genetics PMC - PMC6293052 OTO - NOTNLM OT - cellular stress OT - cystathionine-beta-synthase OT - inflammation OT - muscle atrophy OT - reactive oxygen species EDAT- 2018/08/16 06:00 MHDA- 2019/07/04 06:00 PMCR- 2019/11/01 CRDT- 2018/08/16 06:00 PHST- 2018/08/16 06:00 [pubmed] PHST- 2019/07/04 06:00 [medline] PHST- 2018/08/16 06:00 [entrez] PHST- 2019/11/01 00:00 [pmc-release] AID - C-00147-2018 [pii] AID - 10.1152/ajpcell.00147.2018 [doi] PST - ppublish SO - Am J Physiol Cell Physiol. 2018 Nov 1;315(5):C609-C622. doi: 10.1152/ajpcell.00147.2018. Epub 2018 Aug 15.