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Oral Magnesium Supplementation and Low-Magnitude, High-Frequency Vibration Treatment Attenuate Sarcopenic Muscular Changes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Oral Magnesium Supplementation and Low-Magnitude, High-Frequency Vibration Treatment Attenuate Sarcopenic Muscular Changes./
Author:	Cui, Can.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	177 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
Contained By:	Dissertations Abstracts International83-01B.
Subject:	Physiology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28663003
ISBN:	9798505586822

Oral Magnesium Supplementation and Low-Magnitude, High-Frequency Vibration Treatment Attenuate Sarcopenic Muscular Changes.
Cui, Can.

Oral Magnesium Supplementation and Low-Magnitude, High-Frequency Vibration Treatment Attenuate Sarcopenic Muscular Changes. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 177 p.

Source: Dissertations Abstracts International, Volume: 83-01, Section: B.

Thesis (Ph.D.)--Hong Kong University of Science and Technology (Hong Kong), 2020.

Sarcopenia is an age-related geriatric syndrome which is associated with subsequent disability and morbidity, which is characterized by the gradual loss of muscle mass, muscle strength, and muscle quality in aging. The control of muscle mass is thought to be determined by a dynamic balance of anabolic and catabolic processes, but the key molecular mediators of hypertrophy and atrophy are not yet fully elucidated. Hypertrophy in adult skeletal muscle is accompanied by the increased expression of insulin-like growth factor-1 (IGF-1). The binding of IGF-1 to its receptor triggers the activation of PI3K/Akt pathway, a crucial intracellular signaling mechanism underlying muscle hypertrophy. Low-magnitude high-frequency vibration (LMHFV) is a noninvasive biophysical modality providing cyclic mechanical loading to whole body. LMHFV has been proven to significantly improve the structural and functional outcomes of the skeletal muscle in sarcopenic SAMP8 mice. However, the effect of vibration treatment on muscle mass was negative. As the second most abundant intracellular cation in our body, magnesium (Mg) plays essential roles in various physiological processes in muscle function. Previous studies have already reported that dietary Mg would be associated with better indices of skeletal muscle mass, strength, and power in elder adults, indicating Mg may be a potential resolution for muscle atrophy. The study aims to investigate the effects of LMHFV, Mg and their combination on sarcopenic skeletal muscles and explore the related mechanisms in vivo, as well as the effects on C2C12 myoblast differentiation and myotube fusion via PI3K/Akt/mTOR pathway, thus enhancing myotube hypertrophy in vitro.This study was divided into in vivo and vitro studies. In vivo study, senescence-accelerated mice P8 (SAMP8) at month 6 were randomized into control (Con), vibration (VIB), Mg or Mg+VIB groups. The mice in the VIB group were given LMHFV (0.3g, 35Hz, 20min/day, 5days/week) treatment. Mg was administered to animals through oral gavage of 0.2ml Mg solution in water at the dosage of 200 mg/kg/day, 5 days/week. Both LMHFV and Mg supplement were given to the Mg+VIB group. Ex-vivo functional assessment, immunohistochemical staining of myofibers (myosin heavy chain expression) and dual energy X-ray absorptiometry (DXA) measurements were performed at month 8,9,10 for all groups. The transcriptional expression levels of MyoD, Myf5, Myf6, MuRF1, Muscle atrophy F-box and myogenin (MyoG) were assessed by qPCR; PI3k p85, Akt, pAkt, mTOR protein were detected by Western blot to assess the translational level of PI3k/Akt/mTOR pathway.In vitro, C2C12 myoblasts were cultured on 30mm dishes and fused into myotubes at 70% confluence in DMEM-high glucose medium with 2% non-heat inactivated horse serum. There were 10 groups in this study: (1) control, (2) LMHFV only, (3) Mg only, (4) Mg+LMHFV, (5) Mg+Rapamycin, (6) Mg+LY294002, (7) LMHFV+Rapamycin, (8) LMHFV+LY294002, (8) Mg+LMHFV+Rapamycin (10) Mg+LMHFV+LY29402. The time point at which differentiation was induced was regarded as day 0 (D0). 10mM Mg and LMHFV (35 Hz, 0.3g; 20min/day) were administered on D1; PI3K/Akt inhibitor (20μM LY294002) and mTOR inhibitor (50nm Rapamycin) were added on D3. Myotube formation was examined by immunofluorescence on D5. PI3k/Akt/mTOR translational level was detected by Western blot. Data analysis was performed with one-way ANOVA, and the significant level was set at p≤0.05.In vivo, at late stage in month 9 and 10, lean mass percentage and appendicular lean mass percentage in VIB groups were higher than control group. The mice in the VIB, Mg and combination groups showed significantly higher muscle strength and contractibility at month 9, while Mg group significantly enhanced twitch and tetanic force at month 10. In MHC staining of the gastrocnemius, Mg and the combination groups showed significantly fewer type I muscle fibers and more type IIa and IIb muscle fibers than the control group, while VIB group showed significantly fewer type I muscle fiber percentage. Mg group and the combination group could highly increase the expression level of MyoD, Myf5, and MyoG, and all treatment groups showed significant inhibition effect the expression of MuRF1 and MAFbx. Mg, VIB and combined treatments enhanced expression of signalling molecules of the PI3K/Akt/mTOR signalling pathway. pAkt and mTOR protein expression levels were significantly enhanced by the combination group at early stage of sarcopenia.In vitro, myosin heavy chain (MHC) type IIa expressions in Mg and LMHFV groups were significantly higher than control group, however, co-application of Mg and LMHFV did not show synergistic effect for increasing myotube formation. With the inhibition of PI3k/Akt/mTOR, both LY294002 and Rapamycin groups showed significantly lower myotube formation compared with Mg and LMHFV groups. Inhibition of PI3k/Akt and mTOR abolished the enhancement effects of treatments on MRF expression. Western blot results further substantiated the findings.In this study, the results showed that Mg and LMHFV individually could increase muscle strength and muscle function in vivo, which were also substantiated by some previous studies.There was significant positive association of dietary Mg with indices of skeletal muscle mass and leg explosive power. Similarly, LMHFV was also reported to have positive effects on muscle contractibility and endurance. In our study, it showed that LMHFV could significantly increase muscle mass and muscle strength at month 9 and 10; Mg treatment could increase muscle contractibility and strength at both month 9 and 10 without significant enhancement on muscle mass. This result indicated that Mg and LMHFV individually could accelerate and increase muscle regeneration compared to control group through the PI3k/Akt/mTOR pathway during different sarcopenic stages. Although there was no synergistic effect of combination group on muscle mass or strength in vivo, combination group could highly enhance pAkt and mTOR expression in vivo and vitro, indicating that dietary Mg supplementation and current vibration treatment together could activate downstream of the mechanical loading and muscle hypertrophy pathway. In conclusion, application of LMHFV, Mg could precede sarcopenia related alterations (muscle mass, muscle strength and muscle function) at different sarcopenia stages via PI3k/Akt/mTOR pathway, and there was no synergistic effect of the combination group on sarcopenia muscle in vivo or myotube formation in vitro.

ISBN: 9798505586822Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

Orthopaedics

Oral Magnesium Supplementation and Low-Magnitude, High-Frequency Vibration Treatment Attenuate Sarcopenic Muscular Changes.
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100 1 $a Cui, Can. $3 1267688
245 1 0 $a Oral Magnesium Supplementation and Low-Magnitude, High-Frequency Vibration Treatment Attenuate Sarcopenic Muscular Changes.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 177 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
500 $a Advisor: Li, Gang.
502 $a Thesis (Ph.D.)--Hong Kong University of Science and Technology (Hong Kong), 2020.
520 $a Sarcopenia is an age-related geriatric syndrome which is associated with subsequent disability and morbidity, which is characterized by the gradual loss of muscle mass, muscle strength, and muscle quality in aging. The control of muscle mass is thought to be determined by a dynamic balance of anabolic and catabolic processes, but the key molecular mediators of hypertrophy and atrophy are not yet fully elucidated. Hypertrophy in adult skeletal muscle is accompanied by the increased expression of insulin-like growth factor-1 (IGF-1). The binding of IGF-1 to its receptor triggers the activation of PI3K/Akt pathway, a crucial intracellular signaling mechanism underlying muscle hypertrophy. Low-magnitude high-frequency vibration (LMHFV) is a noninvasive biophysical modality providing cyclic mechanical loading to whole body. LMHFV has been proven to significantly improve the structural and functional outcomes of the skeletal muscle in sarcopenic SAMP8 mice. However, the effect of vibration treatment on muscle mass was negative. As the second most abundant intracellular cation in our body, magnesium (Mg) plays essential roles in various physiological processes in muscle function. Previous studies have already reported that dietary Mg would be associated with better indices of skeletal muscle mass, strength, and power in elder adults, indicating Mg may be a potential resolution for muscle atrophy. The study aims to investigate the effects of LMHFV, Mg and their combination on sarcopenic skeletal muscles and explore the related mechanisms in vivo, as well as the effects on C2C12 myoblast differentiation and myotube fusion via PI3K/Akt/mTOR pathway, thus enhancing myotube hypertrophy in vitro.This study was divided into in vivo and vitro studies. In vivo study, senescence-accelerated mice P8 (SAMP8) at month 6 were randomized into control (Con), vibration (VIB), Mg or Mg+VIB groups. The mice in the VIB group were given LMHFV (0.3g, 35Hz, 20min/day, 5days/week) treatment. Mg was administered to animals through oral gavage of 0.2ml Mg solution in water at the dosage of 200 mg/kg/day, 5 days/week. Both LMHFV and Mg supplement were given to the Mg+VIB group. Ex-vivo functional assessment, immunohistochemical staining of myofibers (myosin heavy chain expression) and dual energy X-ray absorptiometry (DXA) measurements were performed at month 8,9,10 for all groups. The transcriptional expression levels of MyoD, Myf5, Myf6, MuRF1, Muscle atrophy F-box and myogenin (MyoG) were assessed by qPCR; PI3k p85, Akt, pAkt, mTOR protein were detected by Western blot to assess the translational level of PI3k/Akt/mTOR pathway.In vitro, C2C12 myoblasts were cultured on 30mm dishes and fused into myotubes at 70% confluence in DMEM-high glucose medium with 2% non-heat inactivated horse serum. There were 10 groups in this study: (1) control, (2) LMHFV only, (3) Mg only, (4) Mg+LMHFV, (5) Mg+Rapamycin, (6) Mg+LY294002, (7) LMHFV+Rapamycin, (8) LMHFV+LY294002, (8) Mg+LMHFV+Rapamycin (10) Mg+LMHFV+LY29402. The time point at which differentiation was induced was regarded as day 0 (D0). 10mM Mg and LMHFV (35 Hz, 0.3g; 20min/day) were administered on D1; PI3K/Akt inhibitor (20μM LY294002) and mTOR inhibitor (50nm Rapamycin) were added on D3. Myotube formation was examined by immunofluorescence on D5. PI3k/Akt/mTOR translational level was detected by Western blot. Data analysis was performed with one-way ANOVA, and the significant level was set at p≤0.05.In vivo, at late stage in month 9 and 10, lean mass percentage and appendicular lean mass percentage in VIB groups were higher than control group. The mice in the VIB, Mg and combination groups showed significantly higher muscle strength and contractibility at month 9, while Mg group significantly enhanced twitch and tetanic force at month 10. In MHC staining of the gastrocnemius, Mg and the combination groups showed significantly fewer type I muscle fibers and more type IIa and IIb muscle fibers than the control group, while VIB group showed significantly fewer type I muscle fiber percentage. Mg group and the combination group could highly increase the expression level of MyoD, Myf5, and MyoG, and all treatment groups showed significant inhibition effect the expression of MuRF1 and MAFbx. Mg, VIB and combined treatments enhanced expression of signalling molecules of the PI3K/Akt/mTOR signalling pathway. pAkt and mTOR protein expression levels were significantly enhanced by the combination group at early stage of sarcopenia.In vitro, myosin heavy chain (MHC) type IIa expressions in Mg and LMHFV groups were significantly higher than control group, however, co-application of Mg and LMHFV did not show synergistic effect for increasing myotube formation. With the inhibition of PI3k/Akt/mTOR, both LY294002 and Rapamycin groups showed significantly lower myotube formation compared with Mg and LMHFV groups. Inhibition of PI3k/Akt and mTOR abolished the enhancement effects of treatments on MRF expression. Western blot results further substantiated the findings.In this study, the results showed that Mg and LMHFV individually could increase muscle strength and muscle function in vivo, which were also substantiated by some previous studies.There was significant positive association of dietary Mg with indices of skeletal muscle mass and leg explosive power. Similarly, LMHFV was also reported to have positive effects on muscle contractibility and endurance. In our study, it showed that LMHFV could significantly increase muscle mass and muscle strength at month 9 and 10; Mg treatment could increase muscle contractibility and strength at both month 9 and 10 without significant enhancement on muscle mass. This result indicated that Mg and LMHFV individually could accelerate and increase muscle regeneration compared to control group through the PI3k/Akt/mTOR pathway during different sarcopenic stages. Although there was no synergistic effect of combination group on muscle mass or strength in vivo, combination group could highly enhance pAkt and mTOR expression in vivo and vitro, indicating that dietary Mg supplementation and current vibration treatment together could activate downstream of the mechanical loading and muscle hypertrophy pathway. In conclusion, application of LMHFV, Mg could precede sarcopenia related alterations (muscle mass, muscle strength and muscle function) at different sarcopenia stages via PI3k/Akt/mTOR pathway, and there was no synergistic effect of the combination group on sarcopenia muscle in vivo or myotube formation in vitro.
520 $a 歐洲⽼年⼈少肌症⼯作組織(EWGSOP)將少肌症定義為"⾻骼肌量逐漸流失和強度逐漸下降，伴有不良後果如⾝體殘疾，低⽣活質量，甚⾄引起死亡的⼀種綜合征"。肌⾁質量由合成代謝過程和分解代謝過程的動態平衡決定的，但肥⼤和萎縮的關鍵分⼦介質尚未完全闡明。成⼈⾻骼肌肥⼤伴有胰島素樣⽣⾧因⼦-1（IGF-1）表達的增加並激活PI3K/Akt 通路，PI3K/Akt 途徑是肌⾁肥⼤的關鍵細胞內信號傳導機制。低幅⾼頻振動（LMHFV）是⼀種⾮侵⼊性⽣物物理⽅法，可為全⾝提供週期性的機械負荷。鎂（Mg）作為⼈體中第⼆豐富的細胞內陽離⼦，在肌⾁功能的各種⽣理過程中起著⾄關重要的作⽤。這項研究旨在研究LMHFV，Mg 及其組合對⾻骼肌的影響，並探討體內相關機制，以及通過PI3K /Akt/mTOR 途徑對C2C12 成肌細胞分化和肌管融合的影響，從⽽增強肌管肥⼤。在體內研究中，將6 個⽉⼤的SAMP8 ⼩⿏隨機分為對照組（Con），振動組（VIB）， Mg 組(Mg) 和聯合⼲預組（Mg+VIB）。VIB 組的⼩⿏接受了LMHFV（0.3g，35Hz， 20min/day，5days/week）治療。通過⼜服管飼0.2mg Mg ⽔溶液將鎂以200 mg/kg/天，5 天/週的劑量施⽤於動物。LMHFV 和Mg 補充劑均給予Mg+VIB 組。在第8、9、10 個⽉對所有組進⾏了離體肌⾁功能評估，肌纖維的免疫組織化學染⾊和雙能X 線吸收法（DXA）測量。通過qPCR 評估MyoD，Myf5，Myf6，MuRF1，MuRF1 和MAFbx 轉錄表達⽔平；通過蛋⽩質印跡檢測PI3k p85，Akt，pAkt，mTOR 蛋⽩，以評估PI3k / Akt / mTOR 途徑的翻譯⽔平。在體外，C2C12 成肌細胞共分為10 組：（1）對照，（2）僅LMHFV，（3）僅Mg，（4）Mg+LMHFV 組，（5）Mg+雷帕黴素組，（6）Mg+LY294002 組，（7）LMHFV+ 雷帕黴素組，（8）LMHFV+LY294002 組，（8）Mg+LMHFV+雷帕黴素組（10）Mg + LMHFV + LY29402 組。誘導分化的時間點被認為是第0 天（D0）。在第⼀天時進⾏ 10mM Mg 和LMHFV（35 Hz，0.3g; 20min / day）的⼲預；在D3 上加⼊PI3K/Akt 抑製劑（20μm LY294002）和mTOR 抑製劑（50nm 雷帕黴素）。在第五天進⾏免疫熒光染⾊， mRNA 表達分析和蛋⽩質⽔平分析等。⽤單向⽅差分析進⾏數據分析，顯著⽔平設定為 p≤0.05。在體內實驗中，第9 個⽉和第10 個⽉時，VIB 組的全⾝肌⾁質量百分⽐和下肢肌⾁質量百分⽐⾼於對照組。 VIB 組，Mg 組和聯合組的⼩⿏均在第9 個⽉時顯⽰出明顯更⾼的肌⾁⼒量和收縮⼒，⽽Mg 組在第10 個⽉顯⽰痙攣收縮⼒和強直收縮⼒。在MHC 染⾊中，Mg 組和聯合組在第9 和10 個⽉時均顯⽰I 型肌纖維的⽐例明顯少於對照組，⽽IIa 和IIb 型肌纖維則明顯多於對照組。Mg 組和聯合組可顯著提⾼MyoD，Myf5 和MyoG 的 mRNA 相對表達量，並且所有實驗組均可顯著抑制萎縮信號RNA 相關表達量。Mg，VIB 和聯合治療均增強了PI3K/Akt/mTOR 信號通路的信號分⼦的表達。與第8 個⽉和第9 個⽉的對照組相⽐，聯合組顯著增加 pAkt 和mTOR 的蛋⽩相對表達量在體外實驗中，通過計算肌管直徑，肌管內細胞核數等，LMHFV 組，Mg 組和聯合組的肌球蛋⽩重鏈（MHC）IIa 型表達均⽐對照組顯著提⾼。但是，聯合組並無協同作⽤。與Mg 和LMHFV 組相⽐，LY294002 組和雷帕黴素組均顯⽰出明顯較少的肌管形成。 mRNA 表達分析和蛋⽩質印跡結果進⼀步證實了該發現。對PI3K/Akt 和mTOR 通路的抑制抵銷了實驗組的促肌管形成以及促MRF 表達。总结，在我們的研究中，LMHFV 可以顯著增加第9 和10 個⽉的肌⾁質量和肌⾁強度。 Mg 可以在第9 和10 個⽉時候增加肌⾁的收縮和強度，⽽不會明顯增加肌⾁質量。與相應的單⼀處理相⽐，儘管聯合組對體內肌⾁質量或強度沒有協同作⽤，但LMHFV 和 Mg 聯合處理對於pAkt 和mTOR 蛋⽩表達⽔平有顯著的累積效應。因此，根據體內和體外的結果，我們可以推測LMHFV，Mg 的⼲預可以通過PI3K/Akt/mTOR 信號通路增⼤肌⾁質量，提升肌⾁⼒量和肌⾁功能，這種聯合治療可⽤于⽼年相關性少肌症的⼲預。.
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