Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure.

IF 5.3 2区 医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2024-10-18 DOI:10.1186/s13395-024-00354-2
Mamata Chaudhari, Igor Zelko, Pawel Lorkiewicz, David Hoetker, Yibing Nong, Benjamin Doelling, Kenneth Brittian, Aruni Bhatnagar, Sanjay Srivastava, Shahid P Baba
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Abstract

Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS-MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5-2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting.

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心力衰竭时,骨骼肌中清除活性醛的代谢途径会减少。
肌肉萎缩是心力衰竭患者的一种严重并发症。氧化应激和炎症与肌肉萎缩的发病机制有关。氧化应激会形成有毒的脂质过氧化产物,如 4-羟基-2-壬烯醛(HNE),与蛋白质和 DNA 共价结合,激活萎缩途径。在心力衰竭相关的骨骼肌萎缩过程中,脂质过氧化产物的形成以及清除这些有毒产物的代谢途径是否会受到影响,目前还没有人对此进行过研究。雄性 C57BL/6J 小鼠分别接受了 4、8 或 14 周的假手术和横向主动脉收缩(TAC)手术。对不同的骨骼肌床进行称重,并通过免疫组化法测量腓肠肌的总横截面积。肌肉功能和肌肉硬度分别通过握力计和原子力显微镜进行测量。萎缩和炎症标记物水平通过 qRT-PCR 进行测量。腓肠肌中的丙烯醛和 HNE 蛋白加合物、除醛酶、组苷二肽合成酶肌肽合成酶(CARNS)和氨基酸转运体的水平通过 Western 印迹和 qRT-PCR 进行了测定。通过 LC/MS-MS 分析了腓肠肌和比目鱼肌中的组氨酰二肽和组氨酰二肽醛结合物。体重、腓肠肌和比目鱼肌重量以及腓肠肌总横截面积在 TAC 14 周后均有所下降。TAC手术小鼠的心脏重量、心脏功能、握力和肌肉僵硬度均有所下降。TAC 14 周后,腓肠肌中萎缩和炎症标志物 Atrogin1 和 TNF-α 的表达分别增加了 ~ 1.5-2 倍(p
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
期刊最新文献
3D-environment and muscle contraction regulate the heterogeneity of myonuclei. Spiny mice are primed but fail to regenerate volumetric skeletal muscle loss injuries. Decreased number of satellite cells-derived myonuclei in both fast- and slow-twitch muscles in HeyL-KO mice during voluntary running exercise. Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure. Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model.
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