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Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle. 耐缺氧是小鼠屈指肌骨骼肌的固有表型
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-03-21 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad012
Adam J Amorese, Everett C Minchew, Michael D Tarpey, Andrew T Readyoff, Nicholas C Williamson, Cameron A Schmidt, Shawna L McMillin, Emma J Goldberg, Zoe S Terwilliger, Quincy A Spangenburg, Carol A Witczak, Jeffrey J Brault, E Dale Abel, Joseph M McClung, Kelsey H Fisher-Wellman, Espen E Spangenburg

The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O2). Inadequate O2 bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting. Current therapeutic interventions have proven largely ineffective to rescue skeletal muscle from hypoxic damage. However, our lab has identified a mammalian skeletal muscle that maintains proper physiological function in an environment depleted of O2. Using mouse models of in vivo hindlimb ischemia and ex vivo anoxia exposure, we observed the preservation of force production in the flexor digitorum brevis (FDB), while in contrast the extensor digitorum longus (EDL) and soleus muscles suffered loss of force output. Unlike other muscles, we found that the FDB phenotype is not dependent on mitochondria, which partially explains the hypoxia resistance. Muscle proteomes were interrogated using a discovery-based approach, which identified significantly greater expression of the transmembrane glucose transporter GLUT1 in the FDB as compared to the EDL and soleus. Through loss-and-gain-of-function approaches, we determined that GLUT1 is necessary for the FDB to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage. Collectively, the data demonstrate that the FDB is uniquely resistant to hypoxic insults. Defining the mechanisms that explain the phenotype may provide insight towards developing approaches for preventing hypoxia-induced tissue damage.

骨骼肌的各种功能(运动、呼吸、产热等)都需要氧气(O2)的存在。氧气生物利用率不足(即缺氧)会损害肌肉功能,在长期情况下还会导致肌肉萎缩。事实证明,目前的治疗干预措施在很大程度上无法有效拯救缺氧损伤的骨骼肌。然而,我们的实验室发现了一种哺乳动物骨骼肌,它能在缺氧环境中保持正常的生理功能。利用小鼠体内后肢缺血和体外缺氧暴露模型,我们观察到屈指肌(FDB)的力量输出得以保持,相反,伸指肌(EDL)和比目鱼肌的力量输出受到损失。与其他肌肉不同,我们发现 FDB 的表型并不依赖线粒体,这也部分解释了其耐缺氧性。我们使用一种基于发现的方法对肌肉蛋白质组进行了研究,结果发现与 EDL 和比目鱼肌相比,FDB 中跨膜葡萄糖转运体 GLUT1 的表达量明显更高。通过功能缺失和功能获得方法,我们确定 GLUT1 是 FDB 在缺氧条件下存活的必要条件,但过量表达 GLUT1 不足以挽救其他骨骼肌免受缺氧损伤。总之,这些数据证明了 FDB 对缺氧损伤具有独特的抵抗力。确定解释这种表型的机制可能有助于开发预防缺氧引起的组织损伤的方法。
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引用次数: 0
Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently? 内源性ω-3脂肪酸和膳食ω-3脂肪酸酯的作用不同吗?
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-02-23 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad009
Philip C Calder
Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are a family of fatty acids distinguished by the presence of the double bond closest to the methyl terminus of the acyl chain being on carbon number 3 counting from the methyl terminal carbon. There are several members of the ω-3 PUFA family. Usually, the most common ω-3 PUFA in the human diet is α-linolenic acid (ALA; 18:3ω-3), an essential fatty acid made in plants from the ω-6 PUFA linoleic acid (LA; 18:2ω-3) by an enzymatic conversion catalyzed by delta-15 desaturase (Figure 1). Animals do not possess the latter enzyme, so they cannot make ALA. Nevertheless, once consumed in the diet, ALA can be converted by animals into long-chain, more unsaturated ω-3 PUFAs, including eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA: 22:6ω-3) (Figure 1). EPA and DHA are biologically active, influencing cell membrane structure, intracellular signaling pathways, gene expression, and lipid mediator synthesis.1 DPA is less well studied but seems to have similar actions to EPA and DHA. Amongst dietary sources, EPA and DHA are found in the highest amounts in fatty fish; they are also present in fish oil-type supplements. EPA and DHA are linked to many health benefits, including reducing the risk of cardiovascular disease and mortality2; these effects are due to beneficial modification of a number of risk factors.3 There is also evidence that EPA and DHA might reduce the risk of developing nonalcoholic fatty liver disease, through effects on hepatic carbohydrate and fat metabolism and on inflammation.4 In general, case-control studies and longitudinal cohort studies provide stronger evidence for the benefits of EPA and DHA on disease outcomes, with findings from randomized controlled trials in patients at risk of, or already with, disease being inconsistent. Circulating and cell and tissue EPA, DPA, and DHA could come directly from the diet or from endogenous biosynthesis starting with ALA as substrate and using the pathway shown in Figure 1. In people with very low or no intake of seafood and not using supplements that contain EPA, DPA, and DHA, it seems likely that much of the body’s EPA, DPA, and DHA are produced through endogenous biosynthesis.5 Thus, a major role of ALA is as a precursor to its more bioactive ω-3 PUFA derivatives. Endogenous biosynthesis is likely to be downregulated when there is more EPA, DPA, and DHA in the diet.6 However, the relative contributions of diet and endogenous biosynthesis to EPA, DPA, and DHA levels in any compartment or pool within the body are not known. Furthermore, whether the origin of these fatty acids affects their biological action is not well studied. A recent paper published in Function starts to address these questions using murine models.7 Daniel et al.7 use wild-type C57Bl/6 mice and fat-1 mice. The latter are transgenic mice expressing the fat-1 gene from Caenorhabditis elegans, which encodes an enzyme with
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引用次数: 0
BMAL1 in the Adrenal Gland: It's About Time-A Perspective on "Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior". 肾上腺中的 BMAL1:昼夜节律时钟蛋白 BMAL1 的肾上腺特异性 KO 改变了血压节律和进食行为的时间"。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-02-16 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad008
Brittni N Moore, Jennifer L Pluznick
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引用次数: 0
The Gut Microbiome-Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation, and Behavior. 肠道微生物组-内大麻素组轴:控制新陈代谢、炎症和行为的新方法。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-01-12 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad003
Cristoforo Silvestri, Vincenzo Di Marzo
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引用次数: 0
Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior. 肾上腺特异性 KO 昼夜节律时钟蛋白 BMAL1 会改变血压节律和进食行为的时间。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-01-09 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad001
Hannah M Costello, G Ryan Crislip, Kit-Yan Cheng, I Jeanette Lynch, Alexandria Juffre, Phillip Bratanatawira, Annalisse Mckee, Ryanne S Thelwell, Victor M Mendez, Charles S Wingo, Lauren G Douma, Michelle L Gumz

Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global Bmal1 knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific Bmal1 (ASCre/+ ::Bmal1) KO mice were generated using aldosterone synthase Cre recombinase to KO Bmal1 in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male ASCre/+ ::Bmal1 KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. AS Cre/+ ::Bmal1 KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.

脑和肌肉 ARNT 样 1(BMAL1)是一种核心昼夜节律钟蛋白和转录因子,可调节多种生理功能,包括血压(BP)。雄性全基因 Bmal1 敲除(KO)小鼠的血压降低了 10 mmHg,血压节律也变得迟钝。BMAL1 调节血压的机制仍不清楚。肾上腺合成的激素(包括糖皮质激素和矿物质皮质激素)会影响血压节律。为了确定肾上腺 BMAL1 在血压调节中的作用,我们利用醛固酮合成酶 Cre 重组技术在肾上腺肾小球上 KO 了肾上腺特异性 Bmal1(ASCre/+ ::Bmal1 )小鼠。我们证实了 BMAL1 在肾小球肾上腺的定位和 KO 效果。与同窝 Cre- 对照组小鼠相比,雄性 ASCre/+ ::Bmal1 KO 小鼠的血压和活动期/昼夜节律周期(通常为 24 小时)缩短了 ∼ 1 小时,血压和活动的峰值分别延迟了 ∼ 2 小时和 3 小时。只有当 KO 小鼠被关在作为应激源的代谢笼中时,这种差异才会明显,因为与家庭笼相比,代谢笼中的血清皮质酮增加了。AS Cre/+ ::Bmal1 KO小鼠的血清皮质酮昼夜变化也发生了改变。此外,这些小鼠的进食行为也发生了改变,与对照组相比,它们的夜间/白天食物摄入比减弱,但总体食物摄入量没有变化。总之,这些数据表明肾上腺 BMAL1 在调节血压节律和进食行为中发挥作用。
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引用次数: 0
Endothelial Cell Metabolism and Vascular Function: A Paradigm Shift? 内皮细胞代谢与血管功能:范式转变?
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-01-06 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad002
Osama F Harraz
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引用次数: 0
What Does Physiological Mean? 生理是什么意思?
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1093/function/zqad042
Ole H Petersen
S © t a r ecentl y r e vie wed an original paper with a title including he words “physiological stimulation.” In this particular case, t turned out that the stim ulation w as far fr om physiological. he concentration of the hormone used for acti v ation w as w ay bov e the maximal level ever observed in vivo, and this made e think about the use, and misuse, of the word “physiologial.” It is a word that we (physiologists) employ fr equentl y and erhaps too fr equentl y. Papers in physiological, and other, jourals often refer to “physiological conditions,” which sometimes s taken to indicate experiments in vi v o, but also fr equentl y ust means that experiments on single cells or tissue fragents were carried out with stimulation protocols and under ircumstances that are not unlike those that could happen n vi v o. We hav e li v ed thr ough a long and pr oducti v e period of singleell biology. Very important discoveries of real significance have een made, but it is now becoming incr easingl y clear that ther e r e many criticall y important inter actions betw een different djacent cell types in most tissues. To c har acterize these proesses, it is necessary to observe simultaneously more than one ell type in individual organs or tissues. Furthermore, the behavor of a particular cell type in isolation may not be the same as hen it is embedded in its normal environment. Of particular oncern is the tacit assumption in many studies that processes n cell lines reflect those in normal cells in situ. It may therefore e useful to reflect on the usefulness of working under real physological conditions, notwithstanding the obvious difficulties of oing so. In what follows, I’ll try to illuminate these issues by xamples from immunology, epithelial physiology, and neurocience. Ca 2 + signaling studies in imm une cells hav e been immensel y uccessful in unravelling key Ca 2 + transport events and, in articular, the properties of the Ca 2 + r elease acti v ated Ca 2 + CRAC) channel of the Orai type and its molecular control echanism. 1 Unlike the situation in epithelial cells, where Ca 2 +
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引用次数: 0
Watching Ion Channels on the Move. 在移动中观看离子频道。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1093/function/zqac072
Luis A Pardo
Ion channels remain fascinating molecular machines implicated in virtually every cellular function. Their activity can be studied in deep detail using biophysical techniques down to the single-molecule level. However, as large hydrophobic proteins embedded in a lipidic environment, their structure has traditionally been very difficult to study. Cryo-EM approaches have boosted our knowledge in the last few years, expanding the collection of resolved structures almost on a weekly basis. Yet, there are still open questions regarding the structure-function of the channels that are now starting to find answers. Ion channels react rapidly to a wide range of stimuli, opening a pathway for the flow of ions across the membrane. The coupling of the stimulus to the opening of the gate can be studied in ligand-gated channels by comparing the structures of the ligand-bound and unbound channels. Still, such a comparison is more difficult to achieve when the channel responds to physical rather than chemical stimuli, as is the case of voltage-gated channels. The molecular principles of voltage-dependent gating of ion channels have been known for four decades. The mechanism consists, in essence, of the movement of some parts of the protein (the voltage-sensing domains) relative to others. The displacement results in a conformational change that produces the opening of the gate, but the intimate molecular mechanisms linking both events remain only partly known in many cases. Although the problem might appear like an academic discussion for experts at first glance, it has many practical implications. On the one hand—mainly
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引用次数: 0
A Perspective on "Hypoxia Resistance is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle". “耐缺氧是小鼠指屈肌短骨骼肌的一种固有表型”的观点。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1093/function/zqad024
Camila Padilha, Ashleigh M Philp
; Hypoxias; r esistance; inher ent; phenotype; mouse Skeletal muscle is reliant on a constant oxygen supply for mov ement, cellular r espiration, and thermogenesis. Heter oge-neous fibre types exist in skeletal muscle as a continuum from slow- to fast-twitch to facilitate specialized function. Type I (oxidati v e fibr es) pr esent a slow-twitc h phenotype , c har acterized by high oxygen capacity and increased fatigue resistance. In contrast, type IIa (fast oxidati v e gl ycol ytic phenotype) and type IIx (fast gl ycol ytic) pr esent faster twitc h speeds and contr
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引用次数: 0
Redox Bridling of GIRK Channel Activity. GIRK通道活性的氧化还原约束。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1093/function/zqad027
Anna Boccaccio, Rocio K Finol-Urdaneta
pr otein-gated inw ardl y r ectifying potassium (GIRK, Kir3.x) hannels belong to the large family of inw ardl y r ectifying potasium (Kir) channels expressed throughout the body. Activation nd consequent opening of GIRK channels allow inward flow of otassium (K + ) ions into the cell resulting in membrane potenial hyperpolarization and decr eased excita bility. Thus, GIRK hannels play a key role in regulating the activity of neurons and ontrolling important physiological processes including neuonal excita bility, heart r ate , and pain per ception. 1 GIRK channels are integral membrane proteins, existing s homoor heterotetr amers. Eac h monomer features two embrane-spanning helices (M1 and M2), a re-entrant P-loop or controlling ion permeation and selectivity, and extensive ntracellular aminoand carboxy-termini crucial for channel ating. Permeation is regulated by an inner helix gate formed y the M2 segments and a cytoplasmic G-loop gate. 1 Acti v ation of GIRK channels is mediated by the direct interction of G βγ subunits, released from various G protein-coupled ece ptors (GPCRs) upon the acti v ation of inhibitory neuroransmitter r ece ptors. Howev er, the acti vity of GIRK channels epends on the presence of the membrane anionic phospholipid hosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 or PIP 2 ) while it s also modulated by ubiquitously present sodium (Na + ) ions. urthermore , GIRK c hannels ar e too r e gulated by c holesterol, hosphorylation, ethanol, etcetera. 1 The crystal structures of ecombinant GIRK channels have offered valuable insights into ow they are functionally regulated by various ligands. Thus, hannel opening is facilitated by PIP 2 at the plasma membrane, hereas G βγ and Na + modulate the c hannel’s inter action with IP 2 through conformational changes that govern the gating proess. 2 The intracellular milieu is a reducing environment charcterized by a balanced redox state. This state is crucial to upport cellular processes while serving as a pr otecti v e shield
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引用次数: 0
期刊
Function (Oxford, England)
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