Inhibition of the skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity.
Inhibition of the skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity.
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DOI：
10.1002/jcsm.13406
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发表时间：
2024-02
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影响因子：
--
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脂质氢过氧化物（LOOH）与骨骼肌萎缩与年龄和废弃有关。溶血磷脂酰胆碱酰基转移酶3 （LPCAT3）是Lands循环中的一种酶，可将多不饱和脂肪酸酰基链与溶血磷脂偶联，形成含磷脂的多不饱和脂肪酸（PUFA - PL）分子，为LOOH增殖提供底物。以往的研究表明，抑制Lands循环是抑制LOOH的有效策略。使用骨骼肌特异性他莫昔芬诱导敲除LPCAT3 （LPCAT3 - MKO）的小鼠，以确定肌肉特异性loh衰减是否可以减轻肌肉萎缩和无力。LPCAT3‐MKO和对照小鼠接受7天的假手术或后肢卸荷（HU模型）来研究肌肉质量和发力能力。通过定量测定4 -羟基壬烯醛（4 - HNE）偶联肽来评估LOOH。采用定量PCR和脂质谱法验证LPCAT3缺失。7天的HU足以引起肌肉萎缩和虚弱，并伴有4 - HNE增加2倍（P = 0.0069）。LPCAT3的缺失逆转了HU诱导的肌肉4 - HNE的增加（P = 0.0256）。基因型之间在体重、身体成分或热量摄入方面没有发现差异。LPCAT3‐MKO小鼠的比目鱼肌（SOL）和跖肌（PLANT）萎缩程度分别比对照组减少了15%和40%。（P = 0.0011和P = 0.0265）。I型和IIa型SOL肌纤维的横截面面积（CSA）减少了约40%，而在LPCAT3‐MKO小鼠中，这一比例仅为15% （P = 0.0170和P = 0.0411）。引人注目的是，与对照组相比，LPCAT3‐MKO小鼠的SOL肌肉得到了充分的保护，指长伸肌（EDL）肌肉在HU诱导的力产生能力下降中得到了~35%的保护（两种肌肉的P < 0.0001）。我们的研究结果表明，骨骼肌脂质氢过氧化物的衰减足以恢复其功能，特别是防止肌肉比力的减少。我们的研究结果表明，肌肉脂质过氧化有助于小鼠因废用引起的萎缩和虚弱。
Lipid hydroperoxides (LOOH) have been implicated in skeletal muscle atrophy with age and disuse. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme of the Lands cycle, conjugates a polyunsaturated fatty acyl chain to a lysophospholipid to form a polyunsaturated fatty acid containing phospholipid (PUFA‐PL) molecule, providing substrates for LOOH propagation. Previous studies suggest that inhibition of the Lands cycle is an effective strategy to suppress LOOH. Mice with skeletal muscle‐specific tamoxifen‐inducible knockout of LPCAT3 (LPCAT3‐MKO) were utilized to determine if muscle‐specific attenuation of LOOH may alleviate muscle atrophy and weakness with disuse. LPCAT3‐MKO and control mice underwent 7 days of sham or hindlimb unloading (HU model) to study muscle mass and force‐generating capacity. LOOH was assessed by quantifying 4‐hydroxynonenal (4‐HNE)‐conjugated peptides. Quantitative PCR and lipid mass spectrometry were used to validate LPCAT3 deletion. Seven days of HU was sufficient to induce muscle atrophy and weakness concomitant to a ~2‐fold increase in 4‐HNE (P = 0.0069). Deletion of LPCAT3 reversed HU‐induced increase in muscle 4‐HNE (P = 0.0256). No difference was found in body mass, body composition, or caloric intake between genotypes. The soleus (SOL) and plantaris (PLANT) muscles of the LPCAT3‐MKO mice experienced ~15% and ~40% less atrophy than controls, respectively. (P = 0.0011 and P = 0.0265). Type I and IIa SOL myofibers experienced a ~40% decrease in cross sectional area (CSA), which was attenuated to only 15% in the LPCAT3‐MKO mice (P = 0.0170 and P = 0.0411, respectively). Strikingly, SOL muscles were fully protected and extensor digitorum longus (EDL) muscles experienced a ~35% protection from HU‐induced reduction in force‐generating capacity in the LPCAT3‐MKO mice compared with controls (P < 0.0001 for both muscles). Our findings demonstrate that attenuation of skeletal muscle lipid hydroperoxides is sufficient to restore its function, in particular a protection from reduction in muscle specific force. Our findings suggest muscle lipid peroxidation contributes to atrophy and weakness induced by disuse in mice.
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DOI：
10.1002/jcsm.12794
发表时间：
2021-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Lee H;Ha TY;Jung CH;Nirmala FS;Park SY;Huh YH;Ahn J
通讯作者：
Ahn J
DOI：
10.1016/j.biocel.2013.06.011
发表时间：
2013-10
影响因子：
4
作者：
Bodine, Sue C.
通讯作者：
Bodine, Sue C.
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
15.9
作者：
Mezza, Teresa;Ferraro, Pietro Manuel;Giaccari, Andrea
通讯作者：
Giaccari, Andrea