[논문]백지에서 추출한 oxypeucedanin hydrate의 미토콘드리아 기능 관련 근생성 효과

송은주; 허지원; 장지희; 권윤주; 정윤희; 김민정; 김성은

doi:10.4163/jnh.2024.57.1.53

[국내논문] 백지에서 추출한 oxypeucedanin hydrate의 미토콘드리아 기능 관련 근생성 효과
Effects of oxypeucedanin hydrate isolated from Angelica dahurica on myoblast differentiation in association with mitochondrial function 원문보기

Journal of nutrition and health, v.57 no.1, 2024년, pp.53 - 64

송은주 (숙명여자대학교 식품영양학과) , 허지원 (숙명여자대학교 식품영양학과) , 장지희 (숙명여자대학교 생명시스템학부) , 권윤주 (한국한의약진흥원 한약소재개발센터) , 정윤희 (한국한의약진흥원 한약소재개발센터) , 김민정 (숙명여자대학교 생명시스템학부) , 김성은 (숙명여자대학교 식품영양학과)

초록
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본 연구는 근생성 효능을 가진 천연화합물을 발굴하고자 oxypeucedanin hydrate가 근생성과 미토콘드리아에 미치는 영향 및 항암제 유도 미토콘드리아 손상에 대한 완화효과를 C2C12 근원세포와 zebrafish 모델을 통해 각각 확인하였다. 그 결과, oxypeucedanin hydrate는 다핵의 근관세포의 수와 분화말기 표지자인 Myh4의 발현량을 증가시켰고 근육단백질 분해 인자인 MuRF1과 MAFbx의 발현량은 감소시켰다. 또한 미토콘드리아 생합성 조절인자인 Pgc1α, Tfam과 전자전달계 구성인자인 Sdha, Cox1의 발현은 증가시키고, 미토콘드리아 융합인자인 Opa1의 발현 또한 증가시킴과 동시에 미토콘드리아 분열을 표지하는 Drp1의 발현은 감소시켰다. 한편 zebrafish 모델을 통해 항암제 유도 미토콘드리아 손상에 대한 개선효과를 확인한 결과, oxypeucedanin hydrate는 항암제에 의해 유도된 미토콘드리아 손상을 완화시켰다. 이상의 결과들은 oxypeucedanin hydrate가 미토콘드리아 기능 증진을 매개로 근원세포 분화 촉진 및 근육 단백질 분해 저하 효과를 나타냄을 시사한다. 따라서 본 연구를 통해 oxypeucedanin hydrate가 근생성 효과를 나타낼 수 있는 잠재적인 유효소재로서의 가능성을 제시하였다.

Abstract ▼ AI-Helper

Purpose: Mitochondria play a crucial role in preserving skeletal muscle mass, and damage to mitochondria leads to muscle mass loss. This study investigated the effects of oxypeucedanin hydrate, a furanocoumarin isolated from Angelica dahurica radix, on myogenesis and mitochondrial function in vitro and in zebrafish models. Methods: C2C12 myotubes cultured in media containing 0.1, 1, 10, or 100 ng/mL oxypeucedanin hydrate were immunostained with myosin heavy chain (MHC), and then multinucleated MHC-positive cells were counted. The expressions of markers related to muscle differentiation, muscle protein degradation, and mitochondrial function were determined by quantitative reverse transcription polymerase chain reaction. To investigate the effects of oxypeucedanin hydrate on mitochondrial dysfunction, Tg(Xla.Eef1a1:mito-EGFP) zebrafish embryos were treated with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without oxypeucedanin hydrate and analyzed for mito-EGFP intensity and mitochondrial length. Results: Oxypeucedanin hydrate significantly increased MHC-positive multinucleated myotubes (≥ 3 nuclei) and increased the expression of the myogenic marker myosin heavy chain 4. However, it decreased the expressions of muscle-specific RING finger protein 1 and muscle atrophy f-box (markers of muscle protein degradation). Furthermore, oxypeucedanin hydrate enhanced the expressions of markers of mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, transcription factor a mitochondrial, succinate dehydrogenase complex flavoprotein subunit A, and cytochrome c oxidase subunit 1) and mitochondrial fusion (optic atrophy 1). However, it reduced the expression of dynamin-related protein 1 (a mitochondrial fission regulator). Consistently, oxypeucedanin hydrate reduced FOLFIRI-induced mitochondrial dysfunction in the skeletal muscles of zebrafish embryos. Conclusion: The study indicates that oxypeucedanin hydrate promotes myogenesis by improving mitochondrial function, and thus, suggests oxypeucedanin hydrate has potential use as a nutritional supplement that improves muscle mass and function.

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표/그림 (6)

그림 Fig. 1. Oxypeucedanin hydrate extracted from Angelica dahurica radix. (A) Schematic diagram for the oxypeucedanin hydrate isolation protocol. (B) High performance liquid chromatography chromatogram and structure of oxypeucedanin hydrate.
그림 Fig. 2. Effects of OPH on cell viability in C2C12 myoblasts. All data were presented as the mean ± standard error of the mean. Statistical significance was evaluated by oneway analysis of variance followed by Duncan's multiple range test. OPH, oxypeucedanin hydrate.
그림 Fig. 3. Effects of OPH on myotube formation in C2C12 myotubes. (A) Representative immunofluorescence images showing MHC (red-Alexa fluor568) and nuclei (blue-DAPI) (scale bar = 200 μm). (B) Quantification of immunostained C2C12 myotubes. (C-E) The mRNA expression of Myh4, MuRF1, and MAFbx. All data were presented as the mean ± standard error of the mean. Statistical significance was evaluated by Student's t-test (B) or one-way analysis of variance followed by Duncan’s multiple range test (C-E). Values with different letters indicate statistical significance at p < 0.05. OPH, oxypeucedanin hydrate; MHC, myosin heavy chain; DAPI, 4',6-diamidino-2-phenylindole; Myh4, myosin heavy chain 4; MuRF1, muscle-specific RING finger protein 1; MAFbx, muscle atrophy f-box. *p < 0.05, **p < 0.01, ***p < 0.001 vs. control (0 ng/mL).
그림 Fig. 4. Effects of OPH on the mRNA expression of markers involved in mitochondrial biogenesis and mitochondrial dynamics in C2C12 myotubes. (A) Pgc1α; (B) Tfam; (C) Sdha; (D) Cox1; (E) Opa1; (F) Drp1. All data were presented as the mean ± standard error of the mean. Statistical significance was evaluated by one-way analysis of variance followed by Duncan's multiple range test. Values with different letters indicate statistical significance at p < 0.05. OPH, oxypeucedanin hydrate; Pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Tfam, transcription factor a mitochondrial; Sdha, succinate dehydrogenase complex flavoprotein subunit a; Cox1, cytochrome c oxidase subunit 1; Opa1, optic atrophy 1; Drp1, dynamin-related protein 1.
그림 Fig. 5. Effects of OPH on FOLFIRI-induced mitochondrial dysfunction in zebrafish embryos. (A) Representative confocal images showing mitochondrial morphology (scale bar = 20 μm). (B) Quantification of relative intensity of mito-EGFP. (C) Quantitative analysis of mitochondrial length. All data were presented as the mean ± standard error of the mean. Statistical significance was evaluated by Student's t-test or one-way analysis of variance followed by Duncan's multiple range test. Values with different letters indicate statistical significance at p < 0.05. FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; OPH, oxypeucedanin hydrate. *p < 0.05 vs. control (treated without FOLFIRI and OPH).
그림 Fig. 6. Summary of the effects of oxypeucedanin hydrate on muscle differentiation and mitochondrial function. In this study, oxypeucedanin hydrate increased the expression of myogenic marker Myh4, while it reduced the expression of muscle protein degradation markers such as MuRF1 and MAFbx. Also, oxypeucedanin hydrate enhanced the expression of markers involved in mitochondrial biogenesis (Pgc1α, Tfam), fusion (Opa1), and electron transport chain (Sdha, Cox1), whereas it decreased mitochondrial fission marker Drp1 expression. These results demonstrate that oxypeucedanin hydrate promotes myogenesis by improving mitochondrial function. Drp1, dynamin-related protein 1; ETC, electron transport chain; Sdha, succinate dehydrogenase complex flavoprotein subunit a; Cox1, cytochrome c oxidase subunit 1; Opa1, optic atrophy 1; Pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Tfam, transcription factor a mitochondrial; Myh4, myosin heavy chain 4; MuRF1, muscle-specific RING finger protein 1; MAFbx, muscle atrophy f-box. The figure was generated with BioRender (https://biorender.com/).

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