Aerobic Exercise Ameliorates Muscle Atrophy Induced by Methylglyoxal via Increasing Gastrocnemius and Extensor Digitorum Longus Muscle Sensitivity

Hong Seong-Min,Lee Eun Yoo,Park Jinho,Kim Jiyoun,Kim Sun Yeou 한국응용약물학회 2023 Biomolecules & Therapeutics(구 응용약물학회지) Vol.31 No.5

Muscle atrophy is characterized by the loss of muscle function. Many efforts are being made to prevent muscle atrophy, and exercise is an important alternative. Methylglyoxal is a well-known causative agent of metabolic diseases and diabetic complications. This study aimed to evaluate whether methylglyoxal induces muscle atrophy and to evaluate the ameliorative effect of moderateintensity aerobic exercise in a methylglyoxal-induced muscle atrophy animal model. Each mouse was randomly divided into three groups: control, methylglyoxal-treated, and methylglyoxal-treated within aerobic exercise. In the exercise group, each mouse was trained on a treadmill for 2 weeks. On the last day, all groups were evaluated for several atrophic behaviors and skeletal muscles, including the soleus, plantaris, gastrocnemius, and extensor digitorum longus were analyzed. In the exercise group, muscle mass was restored, causing in attenuation of muscle atrophy. The gastrocnemius and extensor digitorum longus muscles showed improved fiber cross-sectional area and reduced myofibrils. Further, they produced regulated atrophy-related proteins (i.e., muscle atrophy F-box, muscle RING-finger protein-1, and myosin heavy chain), indicating that aerobic exercise stimulated their muscle sensitivity to reverse skeletal muscle atrophy. In conclusion, shortness of the gastrocnemius caused by methylglyoxal may induce the dynamic imbalance of skeletal muscle atrophy, thus methylglyoxal may be a key target for treating skeletal muscle atrophy. To this end, aerobic exercise may be a powerful tool for regulating methylglyoxal-induced skeletal muscle atrophy.

골격근 위축에 대한 운동 메커니즘: 기전적 분석

서대윤 ( Dae Yun Seo ),배준현 ( Jun Hyun Bae ),방현석 ( Hyun Seok Bang ),곽이섭 ( Yi Sub Kwak ) 한국운동생리학회(구 한국운동과학회) 2020 운동과학 Vol.29 No.3

PURPOSE: Skeletal muscle atrophy induces overall health problems and many related diseases in older adults. In particular, sarcopenia is related to lowered quality of life, decreased physical activity, high levels of morbidity and mortality owing to chronic diseases, and even falling. Despite the many clinical studies on skeletal muscle atrophy, a little study had been about the exact mechanism of skeletal muscle atrophy at the molecular level. In 2017, A disease code (ICD-10-CM) for skeletal muscle atrophy related to sarcopenia was announced to attempt a clinical approach in the United States. According to these approaches, non-invasive clinical treatment is the most effective method for treating skeletal muscle atrophy. The purpose of this study was to analyze the molecular mechanisms of muscular exercise and related skeletal muscle atrophy factors. METHODS: This systemic review focused on skeletal muscle atrophy and muscular exercise. The keywords were used on “MeSH: muscle atrophy OR skeletal muscle atrophy OR muscle OR atrophy AND physical exercise OR exercise OR exercise training” for English and Korean. This paper searched PubMED, OVIDMEDLINE, and EMBASE for literature consideration. RESULTS: Skeletal muscle atrophy was related to a complex molecular network, and exercise affects IGF-1/Akt/mTOR signaling. The related skeletal muscle atrophy factors were evaluated as MurF1, MAFbx, IGF-1, and NFkB. We proposed new related factors such as ATF 4, Gadd45a, and p21; however, the results related to exercise were not shown in recent studies. CONLCUSIONS: In conclusion, we identified skeletal muscle atrophy factors at the molecular level of muscle physiology, and these new factors may become an interesting field of study in clinical human trial and animal studies.

An herbal formula consisting of <i>Schisandra chinensis</i> (Turcz.) Baill, <i>Lycium chinense</i> Mill and <i>Eucommia ulmoides</i> Oliv alleviates disuse muscle atrophy in rats

Cho, Seongguk,Hong, Riwon,Yim, Poorm,Yeom, Mijung,Lee, Bombi,Yang, Woong Mo,Hong, Jongki,Lee, Hyang Sook,Hahm, Dae–,Hyun Elsevier 2018 Journal of Ethnopharmacology Vol.213 No.-

<P><B>Abstract</B></P> <P><B>Ethnopharmacological relevance</B></P> <P> <I>Schisandra chinensis</I> (Turcz.) Baill (SC), <I>Lycium chinense</I> Mill (LC) and <I>Eucommia ulmoides</I> Oliv (EU) are representative tonic herbal medicines that help to strengthen body muscles and bones making them stronger according to the Donguibogam, a tradition medical book of the Joseon Dynasty in Korea.</P> <P><B>Aim of the study</B></P> <P>To evaluate effects of an herbal formula consisting of SC, LC and EU on muscle atrophy in C2C12 myotubes and in a rat model of immobilization-induced muscle atrophy.</P> <P><B>Materials and methods</B></P> <P>Muscle atrophy was developed by cast immobilization of unilateral hindlimb on rats for 3 weeks. Treatments were administered orally 14 times over 3 weeks. After treatments, we compared the change of body weight, muscle weight, grip strength, muscle fiber size, muscle fiber type shift by Grip strength meter, H&E stain and ATPase stain. And western blot was used for evaluating molecular mechanism in muscle atrophy on C2C12 cells.</P> <P><B>Results</B></P> <P>When taken individually, SC was the most effective of the three in inhibiting tumor necrosis factor alpha (TNF-α)-induced degeneration of C2C12 myogenesis. The formulation with a mass ratio of 2:1:1 SC: LC: EU (SSLE) was more effective against TNF-α-induced muscle atrophy than was a 1:1:1 SC: LC: EU (SLE) formula or any of the single herbal extracts. In a rat model of disuse muscle atrophy, the SSLE formula significantly inhibited reductions in muscle weight, grip strength and muscle fiber size induced by hindlimb immobilization, in a dose-dependent manner. The formula also inhibited immobilization-induced shifting of the muscle fiber type in soleus muscle. Treatment with SSLE inhibited TNF-α-induced expression of the atrogenes atrogin-1 and muscle RING-finger protein 1 in C2C12 cells. The SSLE formula also increased myoblast differentiation markers (myoD and myogenin) and activation of the Akt and mammalian target of rapamycin (mTOR) signaling pathway.</P> <P><B>Conclusion</B></P> <P>These findings suggest that the SSLE formula prevents muscle atrophy through inhibition of the ubiquitin-proteasome system as well as upregulation of myoblast differentiation and muscle protein synthesis in C2C12 cells. Taken together, we conclude that the SSLE formula is invaluable for the development of therapeutic medicines to prevent disuse muscle atrophy and its accompanying muscle weakness.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

<i>Pyropia yezoensis</i> peptide PYP1-5 protects against dexamethasone-induced muscle atrophy through the downregulation of atrogin1/MAFbx and MuRF1 in mouse C2C12 myotubes

Lee, Min-Kyeong,Kim, Young-Min,Kim, In-Hye,Choi, Youn-Hee,Nam, Taek-Jeong SPANDIDOS PUBLICATIONS 2017 MOLECULAR MEDICINE REPORTS Vol.15 No.6

<P>Skeletal muscle atrophy refers to the decline in muscle mass and strength that occurs under various conditions, including aging, starvation, cancer and other cachectic diseases. Muscle atrophy caused by aging, known as sarcopenia, primarily occurs after 50 years of age. Muscle atrophy-related genes, including atrogin1/muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1), are expressed early in the muscle atrophy process, and their expression precedes the loss of muscle mass. The present study investigated the potential anti-atrophic effects of the <I>Pyropia yezoensis</I> peptide PYP1-5. The MTS assay did not detect cytotoxic effects of PYP1-5 on C2C12 mouse myoblast cells. Subsequently, the anti-atrophic effects of PYP1-5 on skeletal muscle cells was examined by treating C2C12 myotubes with 100 µM dexamethasone (DEX) and/or 500 ng/ml PYP1-5 for 24 h. Compared with the control, myotube diameter was reduced in DEX-treated cells, whereas PYP1-5 treatment protected against DEX-induced muscle atrophy. MAFbx and MuRF1 protein and mRNA expression levels were detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction, respectively. The results demonstrated that PYP1-5 significantly reduced the expression of atrogin1/MAFbx and MuRF1. Therefore, data from the present study suggest that PYP1-5 inhibits the expression of atrogin1/MAFbx and MuRF1 in C2C12 cells, and these characteristics may be of value in the development of anti-atrophy functional foods.</P>

발아 서목태 가수분해물의 근위축 억제 효과

이원경,김은지,김상곤,구영민,길영숙,신승미,안민주,강민철,하영술 한국생명과학회 2023 생명과학회지 Vol.33 No.3

Sarcopenia is the age-related loss of muscle mass and function. It is a natural part of aging and can lead to decreased mobility and increased frailty. The ubiquitin-proteasome pathway, which is involved in muscle protein degradation, is closely linked to sarcopenia. Germinated Rhynchosia nulubilis hydrolysate (GRH) has been reported to have anti-inflammatory and antioxidant properties, but there have been no reports on its inhibitory effect on muscle reduction. However, no study has yet explored the relationship between GRH and muscle loss inhibition. In this study, we evaluated the effects of GRH on muscle atrophy inhibitory activity in dexamethasone (Dexa)-induced muscle atrophy C2C12 myotubes and mouse models. Moreover, we identified a molecular pathway underlying the effects of GRH on skeletal muscle. May Grunwald-Giemsa staining showed that the length and area of myotubes increased in the groups treated with GRH. In addition, the GRH-treated group significantly reduced the expression of muscle ring finger protein 1 and muscular atrophy F-box (MAFbx) in the Dexa-induced muscular atrophy C2C12 model. GRH also improved muscle strength in C57BL/6 mice with Dexa-induced muscle atrophy, resulting in prolonged running exhaustive time and increased grip strength. We found that muscle strengthening by GRH was correlated with a decreased expression of the MAFbx gene in mouse muscle tissue. In conclusion, GRH can attenuate Dexa-induced muscle atrophy by inhibiting the ubiquitin-proteasome pathway via downregulation of the MAFbx gene expression.

콩잎 추출물의 근위축 개선 효과

최혜영(Hye Young Choi),하영술(Young-Sool Hah),지영호(Yeong Ho Ji),하준영(Jun Young Ha),배환희(Hwan Hee Bae),이동열(Dong Yeol Lee),정원민(Won Min Jeong),정동규(Dong Kyu Jeong),유준일(Jun-Il Yoo),김상곤(Sang Gon Kim) 한국생명과학회 2023 생명과학회지 Vol.33 No.12

골격근량과 근력의 점진적인 감소를 특징으로 하는 근감소증은 고령화 인구에서 중요한 문제이다. 본 연구는 콩잎 추출물(Soybean Leaf extracts, SL)의 덱사메타손으로 유도된 근위축에 대한 치료적 가능성을 세포 및 동물 모델에서 조사하였다. 세포 실험 결과, SL은 C2C12 근섬유의 형태, 밀도 및 크기가 보존되어 통계적으로 유의미한 수준으로 덱사메타손에 의해 유발된 근위축을 완화하는 것으로 나타났다. 또한, SL 처리는 주요 근육 위축 조절 인자인 muscle RING-finger protein-1 (MuRF1)과 muscle atrophy F-box (MAFbx)의 발현을 mRNA 및 단백질 수준 모두에서 유의하게 하향 조절하였다. 마우스 모델에서 SL 투여는 특히 덱사메타손으로 인한 체중 감소와 근육 소모를 상쇄하여 비복근과 전경골근의 근육량을 보존하는 것으로 나타났다. 기능적으로도 SL을 투여한 마우스는 악력과 트레드밀 지구력이 향상되어 근육 성능이 개선되었다. 또한 SL은 골격근에서 근위축 관련 단백질인 MAFbx의 발현을 억제하여 덱사메타손 유도 근위축에 대한 보호 역할을 보여주었다. 이러한 연구 결과를 종합해 볼 때 SL은 근감소증과 같은 근육 소모 질환을 개선할 수 있는 유망한 천연 치료제가 될 수 있음을 시사한다. Sarcopenia, a condition characterized by the insidious loss of skeletal muscle mass and strength, represents a significant and growing healthcare challenge, impacting the mobility and quality of life of aging populations worldwide. This study investigated the therapeutic potential of soybean leaf extract (SL) for dexamethasone (Dexa)-induced muscle atrophy in vitro and in an in vivo model. In vitro experiments showed that SL significantly alleviated Dexa-induced atrophy in C2C12 myotube cells, as evidenced by preserved myotube morphology, density, and size. Moreover, SL treatment significantly reduced the mRNA and protein levels of muscle RING-finger protein-1 (MuRF1) and muscle atrophy F-box (MAFbx), key factors regulating muscle atrophy. In a Dexa-induced atrophy mouse model, SL administration significantly inhibited Dexa-induced weight loss and muscle wasting, preserving the mass of the gastrocnemius and tibialis anterior muscles. Furthermore, mice treated with SL exhibited significant improvements in muscle function compared to their counterparts suffering from Dexa-induced muscle atrophy, as evidenced by a notable increase in grip strength and extended endurance on treadmill tests. Moreover, SL suppressed the expression of muscle atrophy–related proteins in skeletal muscle, highlighting its protective role against Dexa-induced muscle atrophy. These results suggest that SL has potential as a natural treatment for muscle-wasting conditions, such as sarcopenia.

C2C12 근관세포에서 dexamethasone 및 hydrogen peroxide에 의한 근위축 유도

박철(Cheol Park),정진우(Jin-Woo Jeong),최영현(Yung Hyun Choi) 한국생명과학회 2017 생명과학회지 Vol.27 No.12

일반적으로 노화, 영양부족 및 다양한 만성질환에 의하여 유발되는 근위축은 근육 단백질 합성 억제 및 분해 증가를 통하여 근섬유 및 근육의 밀도를 감소시키는 것으로 알려져 있다. 본 연구에서는 근위축과 관련된 in vitro실험을 위한 C2C12 근아세포에서 근관세포로의 분화과정을 확립하고, 분화가 유발된 C2C12 근관세포를 대상으로 dexamethasone 및 hydrogen peroxide에 의한 근위축 유발 및 관련 단백질들의 발현 변화를 조사하였다. 먼저 C2C12 근아세포에 분화배지를 처리하였을 경우 근관세포로 분화가 유발되었으며, 분화와 관련된 단백질인 myogenin 및 myoD의 발현이 증가하는 것으로 나타났다. 분화가 유발된 C2C12 근관세포에 세포독성이 없는 조건의 dexamethasone 및 hydrogen peroxide를 처리하였을 경우 근관의 지름이 감소하였으며, 이러한 현상은 musclespecific ubiquitin ligases인 MAFbx/atrogin-1 및 MuRF1의 발현 증가와 함께 muscle-specific transcription factor인 myogenin 및 MyoD의 발현 감소와 관련이 있다는 것을 확인하였다. 본 연구 결과는 근위축과 관련된 in vitro 실험 모델의 구축을 위한 최적의 분화조건 확립과 함께 dexamethasone 및 hydrogen peroxide를 근위축 유도제로 사용할 수 있는 가능성 을 제시하는 것이다. Muscle atrophy due to aging, starvation, and various chronic diseases leads to a decrease in muscle fiber area and density due to reduced muscle protein synthesis and increased protein breakdown. This study investigated the effect of dexamethasone and hydrogen peroxide on the induction of muscle atrophy and expression of atrophy-related genes in differentiated C2C12 myotubes. C2C12 myoblasts were differentiated into myotubes in differentiation medium. During myoblast differentiation, muscle-specific transcription factors, such as myogenin, and MyoD expression increased. Differentiated C2C12 myotubes exposed to noncytotoxic levels of dexamethasone and hydrogen peroxide showed a decrease in myotube diameter, which was associated with up-regulation of muscle-specific ubiquitin ligases, such as muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), and down-regulation of myogenin and MyoD. These results demonstrated that dexamethasone and hydrogen peroxide induced atrophy through regulation of muscle-specific ubiquitin ligases and muscle-specific transcription factors in C2C12 myotubes. In this study, we confirmed the process of differentiation of C2C12 myoblasts into myotubes in in vitro experiments in the presence of atrophy. This muscle atrophy model of C2C12 cells induced by dexamethasone or hydrogen peroxide seems suited to studies of the mechanism of muscle atrophy suppression and to exploit the experiment for excavating new muscle atrophy.

Beneficial effects of melatonin on stroke-induced muscle atrophy in focal cerebral ischemic rats

Seunghoon Lee,Jinhee Shin,Yunkyung Hong,Minkyung Lee,Koo Kim,Sang-Rae Lee,Kyu-Tae Chang,Yonggeun Hong 한국실험동물학회 2012 Laboratory Animal Research Vol.28 No.1

Muscle atrophy is the result of two opposing conditions that can be found in pathological or diseased muscles: an imbalance in protein synthesis and degradation mechanisms. Thus, we investigated whether exogenous melatonin could regulate muscle components in stroke-induced muscle atrophy in rats. Comparing muscle phenotypes, we found that long-term melatonin administration could influence muscle mass. Muscle atrophy-related genes, including muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1) were significantly down-regulated in melatonin-administered rats in the gastrocnemius. However, only MAFbx at the mRNA level was attenuated in the soleus of melatonin-administered rats. Insulin-like growth factor-1 receptor (IGF-1R) was significantly over-expressed in melatonin-administered rats in both the gastrocnemius and soleus muscles. Comparing myosin heavy chain (MHC) components, in the gastrocnemius, expression of both slow- and fast-type isoforms were significantly enhanced in melatoninadministered rats. These results suggest that long-term exogenous melatonin administration may have a prophylactic effect on muscle atrophy through the MuRF1/MAFbx signaling pathway, as well as a potential therapeutic effect on muscle atrophy through the IGF-1-mediated hypertrophic signaling pathway in a stroke animal model.

근위축 마우스 모델에서 한국산 겨우살이 추출물에 의한 단백질 합성 신호전달 경로의 활성화

정주성 ( Juseong Jeong ),박춘호 ( Choon-ho Park ),김인보 ( Inbo Kim ),김종배 ( Jong-bae Kim ) 한국식품영양학회 2017 韓國食品營養學會誌 Vol.30 No.2

Muscle atrophy is characterized by a decrease in the mass of the muscle. With an increase in life expectancy and chronic illnesses, the incidence of muscle atrophy is increasing and the quality of life of patients is decreasing. Thus, reducing muscle atrophy is of high clinical and socio-economic importance. Mistletoe is a semi-parasitic plant that has been used as a traditional medicine in many countries to treat various human illnesses. It has been reported that Korean mistletoe extract (KME) has diverse biological functions including anti-tumor, anti-oxidant, anti-diabetic, anti-obesity properties, and extension of lifespan. Especially, we have recently reported that KME improves exercise endurance in mice, indicating its beneficial roles in enhancing the capacity of skeletal muscle. In this study, we investigated whether KME could activate the signaling pathway related to protein synthesis in a mouse model of muscle atrophy. Interestingly, KME efficiently activated the Akt/mTOR pathway, and Akt and mTOR are important signaling hub molecules for the acceleration of protein synthesis in muscle cells. In addition, KME also increased the activity of S6 kinase which is involved in the regulation of muscle cell size. Moreover, the ERK activity, required for transcription of ribosomal RNA for protein synthesis, was also enhanced in KME-treated mouse muscle. These data support the idea that KME increases muscle mass via increased protein synthesis. Our findings also suggest that Korean mistletoe might be a promising candidate for the development of functional foods that are beneficial for preventing muscle atrophy.

A Mixture of Morus alba and Angelica keiskei Leaf Extracts Improves Muscle Atrophy by Activating the PI3K/Akt/mTOR Signaling Pathway and Inhibiting FoxO3a In Vitro and In Vivo

Hwangbo Hyun,Kim Min Yeong,Ji Seon Yeong,Kim Da Hye,Park Beom Su,Jeong Seong Un,Yoon Jae Hyun,Kim Tae Hee,Kim Gi-Young,Choi Yung Hyun 한국미생물·생명공학회 2023 Journal of microbiology and biotechnology Vol.33 No.12

Muscle atrophy, which is defined as a decrease in muscle mass and strength, is caused by an imbalance between the anabolism and catabolism of muscle proteins. Thus, modulating the homeostasis between muscle protein synthesis and degradation represents an efficient treatment approach for this condition. In the present study, the protective effects against muscle atrophy of ethanol extracts of Morus alba L. (MA) and Angelica keiskei Koidz. (AK) leaves and their mixtures (MIX) were evaluated in vitro and in vivo. Our results showed that MIX increased 5-aminoimidazole4-carboxamide ribonucleotide-induced C2C12 myotube thinning, and enhanced soleus and gastrocnemius muscle thickness compared to each extract alone in dexamethasone-induced muscle atrophy Sprague Dawley rats. In addition, although MA and AK substantially improved grip strength and histological changes for dexamethasone-induced muscle atrophy in vivo, the efficacy was superior in the MIX-treated group. Moreover, MIX further increased the expression levels of myogenic factors (MyoD and myogenin) and decreased the expression levels of E3 ubiquitin ligases (atrogin-1 and muscle-specific RING finger protein-1) in vitro and in vivo compared to the MA- and AK-alone treatment groups. Furthermore, MIX increased the levels of phosphorylated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) that were reduced by dexamethasone, and downregulated the expression of forkhead box O3 (FoxO3a) induced by dexamethasone. These results suggest that MIX has a protective effect against muscle atrophy by enhancing muscle protein anabolism through the activation of the PI3K/Akt/mTOR signaling pathway and attenuating catabolism through the inhibition of FoxO3a.