Pub Date : 2024-03-26DOI: 10.1093/function/zqae014
Simon Schenk, Tyler J. Sagendorf, Gina Many, Ana K Lira, Gustavo DeSousa, Dam Bae, Michael Cicha, Kyle S Kramer, Michael Muehlbauer, Andrea L Hevener, R. Rector, John P Thyfault, John P Williams, Laurie J. Goodyear, Karyn A. Esser, Christopher B. Newgard, Sue C. Bodine, Joshua N Adkins, Brent G. Albertson, David Amar, M. A. Amper, Euan Ashley, Dam Bae, M. Bamman, Jerry Barnes, Bryan C Bergman, Daniel H. Bessesen, Sue C. Bodine, T. Buford, Charles F. Burant, Michael Cicha, G. Cutter, Luis Oliveria De Sousa, Karyn A. Esser, Facundo M. Fernández, David A. Gaul, Y. Ge, Bret H. Goodpaster, Laurie J. Goodyear, Kristen Guevara, Andrea L Hevener, M. Hirshman, Kim M. Huffman, Bailey E. Jackson, Catherine M. Jankowski, D. Jimenez-Morales, W. Kohrt, Kyle S Kramer, William E. Kraus, S. Lessard, Bridget Lester, Maléne E. Lindholm, Ana K Lira, Gina Many, Nada Marjanović, A. Marshall, Edward L. Melanson, Michael E Miller, K. Moreau, V. Nair, Christopher B. Newgard, E. Ortlund, Wei-Jun Qian, Blake B Rasmussen, R. Rector,
While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-month) and Aged (18-month) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 days/week, ∼70–75% VO2max) for 1, 2, 4, or 8 weeks; sedentary rats were studied as the control group. Eighteen solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1–2 weeks and improvements in maximum run speed and maximal oxygen uptake by 4–8 weeks. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a pre-clinical rat model.
{"title":"Physiological Adaptations to Progressive Endurance Exercise Training in Adult And Aged Rats: Insights from The Molecular Transducers of Physical Activity Consortium (MoTrPAC)","authors":"Simon Schenk, Tyler J. Sagendorf, Gina Many, Ana K Lira, Gustavo DeSousa, Dam Bae, Michael Cicha, Kyle S Kramer, Michael Muehlbauer, Andrea L Hevener, R. Rector, John P Thyfault, John P Williams, Laurie J. Goodyear, Karyn A. Esser, Christopher B. Newgard, Sue C. Bodine, Joshua N Adkins, Brent G. Albertson, David Amar, M. A. Amper, Euan Ashley, Dam Bae, M. Bamman, Jerry Barnes, Bryan C Bergman, Daniel H. Bessesen, Sue C. Bodine, T. Buford, Charles F. Burant, Michael Cicha, G. Cutter, Luis Oliveria De Sousa, Karyn A. Esser, Facundo M. Fernández, David A. Gaul, Y. Ge, Bret H. Goodpaster, Laurie J. Goodyear, Kristen Guevara, Andrea L Hevener, M. Hirshman, Kim M. Huffman, Bailey E. Jackson, Catherine M. Jankowski, D. Jimenez-Morales, W. Kohrt, Kyle S Kramer, William E. Kraus, S. Lessard, Bridget Lester, Maléne E. Lindholm, Ana K Lira, Gina Many, Nada Marjanović, A. Marshall, Edward L. Melanson, Michael E Miller, K. Moreau, V. Nair, Christopher B. Newgard, E. Ortlund, Wei-Jun Qian, Blake B Rasmussen, R. Rector,","doi":"10.1093/function/zqae014","DOIUrl":"https://doi.org/10.1093/function/zqae014","url":null,"abstract":"\u0000 While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-month) and Aged (18-month) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 days/week, ∼70–75% VO2max) for 1, 2, 4, or 8 weeks; sedentary rats were studied as the control group. Eighteen solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1–2 weeks and improvements in maximum run speed and maximal oxygen uptake by 4–8 weeks. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a pre-clinical rat model.","PeriodicalId":503843,"journal":{"name":"Function","volume":"119 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140380081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-14DOI: 10.1093/function/zqae013
H. Watanabe, Yaromir Kobikov, O. Nosova, D. Sarkisyan, Vladimir Galatenko, Liliana Carvalho, Gisela H Maia, Nikolay Lukoyanov, Igor Lavrov, Michael H Ossipov, Mathias Hallberg, Jens Schouenborg, Mengliang Zhang, Georgy Bakalkin
A neurological dogma is that the contralateral effects of brain injury are set through crossed descending neural tracts. We have recently identified a novel topographic neuroendocrine system (T-NES) that operates via a humoral pathway and mediates the left-right side-specific effects of unilateral brain lesions. In rats with completely transected thoracic spinal cords, unilateral injury to the hindlimb sensorimotor cortex produced hindlimb postural asymmetry with contralateral hindlimb flexion, a proxy for neurological deficit. Here, we investigated in acute experiments whether T-NES consists of left and right counterparts and whether they differ in neural and molecular mechanisms and their operating patterns, which may be ipsi- or contra-lateral relative to the side of brain injury. We demonstrated that left and right-sided hormonal signaling is differentially blocked by the selective opioid antagonists. The effects of the left-brain lesion were inhibited by antagonists of the δ- and κ-opioid receptors, whereas those of the right brain lesion were inhibited by a µ-opioid antagonist. Left and right neurohormonal signaling differed in targeting the afferent spinal mechanisms. Bilateral deafferentation of the lumbar spinal cord abolished the hormone-mediated effects of the left-brain injury but not the right-sided lesion. The sympathetic nervous system was ruled out as a brain-to-spinal cord signaling pathway since the hindlimb responses were induced in rats with cervical spinal cord transections that were rostral to the preganglionic sympathetic neurons. Analysis of gene-gene co-expression patterns identified the left- and right-side-specific gene regulatory networks that were coordinated via the humoral pathway across the hypothalamus and lumbar spinal cord. The coordination was ipsilateral and disrupted by brain injury. These findings suggest that T-NES is bipartite, and that its left and right counterparts contribute to contralateral neurological deficits through distinct neural mechanisms, and may enable ipsilateral regulation of molecular and neural processes across distant neural areas along the neuraxis.
{"title":"The left-right side-specific neuroendocrine signaling from injured brain: an organizational principle","authors":"H. Watanabe, Yaromir Kobikov, O. Nosova, D. Sarkisyan, Vladimir Galatenko, Liliana Carvalho, Gisela H Maia, Nikolay Lukoyanov, Igor Lavrov, Michael H Ossipov, Mathias Hallberg, Jens Schouenborg, Mengliang Zhang, Georgy Bakalkin","doi":"10.1093/function/zqae013","DOIUrl":"https://doi.org/10.1093/function/zqae013","url":null,"abstract":"\u0000 A neurological dogma is that the contralateral effects of brain injury are set through crossed descending neural tracts. We have recently identified a novel topographic neuroendocrine system (T-NES) that operates via a humoral pathway and mediates the left-right side-specific effects of unilateral brain lesions. In rats with completely transected thoracic spinal cords, unilateral injury to the hindlimb sensorimotor cortex produced hindlimb postural asymmetry with contralateral hindlimb flexion, a proxy for neurological deficit. Here, we investigated in acute experiments whether T-NES consists of left and right counterparts and whether they differ in neural and molecular mechanisms and their operating patterns, which may be ipsi- or contra-lateral relative to the side of brain injury. We demonstrated that left and right-sided hormonal signaling is differentially blocked by the selective opioid antagonists. The effects of the left-brain lesion were inhibited by antagonists of the δ- and κ-opioid receptors, whereas those of the right brain lesion were inhibited by a µ-opioid antagonist. Left and right neurohormonal signaling differed in targeting the afferent spinal mechanisms. Bilateral deafferentation of the lumbar spinal cord abolished the hormone-mediated effects of the left-brain injury but not the right-sided lesion. The sympathetic nervous system was ruled out as a brain-to-spinal cord signaling pathway since the hindlimb responses were induced in rats with cervical spinal cord transections that were rostral to the preganglionic sympathetic neurons. Analysis of gene-gene co-expression patterns identified the left- and right-side-specific gene regulatory networks that were coordinated via the humoral pathway across the hypothalamus and lumbar spinal cord. The coordination was ipsilateral and disrupted by brain injury. These findings suggest that T-NES is bipartite, and that its left and right counterparts contribute to contralateral neurological deficits through distinct neural mechanisms, and may enable ipsilateral regulation of molecular and neural processes across distant neural areas along the neuraxis.","PeriodicalId":503843,"journal":{"name":"Function","volume":"11 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140243588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-07DOI: 10.1093/function/zqae011
J. Huot, Patrick D Livingston, Fabrizio Pin, Connor R Thomas, Nicholas A Jamnick, Chandler S Callaway, A. Bonetto
Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 weeks. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 weeks after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 weeks after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data supports that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.
{"title":"Long-term musculoskeletal consequences of chemotherapy in pediatric mice","authors":"J. Huot, Patrick D Livingston, Fabrizio Pin, Connor R Thomas, Nicholas A Jamnick, Chandler S Callaway, A. Bonetto","doi":"10.1093/function/zqae011","DOIUrl":"https://doi.org/10.1093/function/zqae011","url":null,"abstract":"\u0000 Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 weeks. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 weeks after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 weeks after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data supports that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.","PeriodicalId":503843,"journal":{"name":"Function","volume":"48 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140259210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-28DOI: 10.1093/function/zqae009
Mrunmayee R Kandalgaonkar, B. Yeoh, B. Joe, Nathan W. Schmidt, M. Vijay-Kumar, P. Saha
Global prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBC are target host cells for malarial parasite, Plasmodium, we hypothesized that hypertensive patients with abnormal RBC physiology are at greater risk or susceptibility to Plasmodium infection. To test this hypothesis, normotensive (BPN/3 J) and hypertensive (BPH/2 J) mice were characterized for their RBC physiology and subsequently infected with Plasmodium yoelii (P. yoelii), a murine-specific non-lethal strain. When compared to BPN mice, BPH mice displayed microcytic anemia and their RBC were highly resistant to osmotic hemolysis. Further, BPH RBC exhibited an increase in membrane rigidity and an altered lipid composition, as evidenced by higher levels of phospholipids and saturated fatty acid, such as stearate (C18:0), along with lower levels of polyunsaturated fatty acid like arachidonate (C20:4). Moreover, BPH mice had significantly greater circulating Ter119+ CD71+ reticulocytes, or immature RBC, prone to P. yoelii infection. Upon infection with P. yoelii, BPH mice experienced significant body weight loss accompanied by sustained parasitemia, indices of anemia, and substantial increase in systemic pro-inflammatory mediators, compared to BPN mice, indicating that BPH mice were incompetent to clear P. yoelii infection. Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive BPH mice contributes to an increased susceptibility to P. yoelii infection and malaria-associated pathology.
全球高血压发病率呈上升趋势,给医疗保健带来了沉重负担,尤其是在疟疾等传染病肆虐的发展中国家。然而,高血压是否会导致或增加疟疾的易感性还没有得到广泛的探讨。此前,我们曾报道过高血压与红细胞(RBC)生理异常和贫血有关。由于红细胞是疟原虫疟原虫的靶宿主细胞,我们假设红细胞生理异常的高血压患者感染疟原虫的风险或易感性更高。为了验证这一假设,我们对正常血压(BPN/3 J)和高血压(BPH/2 J)小鼠的红细胞生理学进行了鉴定,随后用一种小鼠特异性非致死株疟原虫(P. yoelii)进行了感染。与 BPN 小鼠相比,BPH 小鼠表现出微量红细胞性贫血,其红细胞对渗透性溶血具有很强的抵抗力。此外,BPH 小鼠的红细胞膜刚性增加,脂质组成发生改变,表现为磷脂和饱和脂肪酸(如硬脂酸(C18:0))含量增加,而多不饱和脂肪酸(如花生四烯酸(C20:4))含量降低。此外,BPH小鼠循环中的Ter119+ CD71+网织红细胞或未成熟红细胞明显增多,易受酵母疽感染。与 BPN 小鼠相比,BPH 小鼠在感染 P. yoelii 后体重明显下降,并伴有持续的寄生虫血症、贫血指数和全身促炎介质的大量增加,这表明 BPH 小鼠没有能力清除 P. yoelii 感染。总之,这些数据表明,在高血压 BPH 小鼠体内观察到的异常红细胞生理机能导致其对 P. yoelii 感染和疟疾相关病理的易感性增加。
{"title":"Hypertension Increases Susceptibility to Experimental Malaria in Mice","authors":"Mrunmayee R Kandalgaonkar, B. Yeoh, B. Joe, Nathan W. Schmidt, M. Vijay-Kumar, P. Saha","doi":"10.1093/function/zqae009","DOIUrl":"https://doi.org/10.1093/function/zqae009","url":null,"abstract":"\u0000 Global prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBC are target host cells for malarial parasite, Plasmodium, we hypothesized that hypertensive patients with abnormal RBC physiology are at greater risk or susceptibility to Plasmodium infection. To test this hypothesis, normotensive (BPN/3 J) and hypertensive (BPH/2 J) mice were characterized for their RBC physiology and subsequently infected with Plasmodium yoelii (P. yoelii), a murine-specific non-lethal strain. When compared to BPN mice, BPH mice displayed microcytic anemia and their RBC were highly resistant to osmotic hemolysis. Further, BPH RBC exhibited an increase in membrane rigidity and an altered lipid composition, as evidenced by higher levels of phospholipids and saturated fatty acid, such as stearate (C18:0), along with lower levels of polyunsaturated fatty acid like arachidonate (C20:4). Moreover, BPH mice had significantly greater circulating Ter119+ CD71+ reticulocytes, or immature RBC, prone to P. yoelii infection. Upon infection with P. yoelii, BPH mice experienced significant body weight loss accompanied by sustained parasitemia, indices of anemia, and substantial increase in systemic pro-inflammatory mediators, compared to BPN mice, indicating that BPH mice were incompetent to clear P. yoelii infection. Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive BPH mice contributes to an increased susceptibility to P. yoelii infection and malaria-associated pathology.","PeriodicalId":503843,"journal":{"name":"Function","volume":"278 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140420940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22DOI: 10.1093/function/zqae010
Olalla Colinas, Peter Mombaerts, J. López-Barneo, Patricia Ortega-Sáenz
The Olfr78 gene encodes a G-protein coupled receptor that is expressed in olfactory sensory neurons, where it functions as a conventional odorant receptor, and also in several ectopic sites, where its function is not well understood. Olfr78 is one of the most highly expressed mRNA species in glomus cells of the carotid body (CB). These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in Olfr78 knockout mice. In another study, Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. These organismal phenotypes could result from pleiotropic effects of the constitutive Olfr78 knockout mutations in the various CB cell types and/or various organs where this gene is expressed. Therefore, to further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for the phenotypic specification of mature glomus cells.
Olfr78 基因编码一种 G 蛋白偶联受体,该受体在嗅觉神经元中表达,在嗅觉神经元中起传统气味受体的作用,同时也在几个异位位点中表达,其功能尚不十分清楚。Olfr78 是颈动脉体(CB)神经胶质细胞中表达量最高的 mRNA 物种之一。这些细胞是典型的对氧气(O2)敏感的动脉化学感受器,当氧气张力降低(缺氧)时,它们会激活呼吸中枢,诱导过度换气。有人提出,Olfr78 是一种乳酸受体,血液中乳酸的增加会激活神经胶质细胞,从而介导缺氧通气反应(HVR)。然而,一些研究小组对这一提议提出了质疑,他们的研究表明,Olfr78 并非生理上相关的乳酸受体,Olfr78 基因敲除小鼠基于氧气的呼吸调节并不受影响。另一项研究报告称,Olfr78基因敲除小鼠对轻度缺氧的全身反应和CB反应发生了改变。这些机体表型可能是由于组成型 Olfr78 基因敲除突变在各种 CB 细胞类型和/或该基因表达的各种器官中产生的多效应。因此,为了进一步确定Olfr78在CB胶束细胞中的功能作用,我们在这里产生了一个条件性Olfr78基因敲除小鼠品系,然后通过与酪氨酸羟化酶特异性Cre驱动品系杂交(TH-Olfr78 KO小鼠),将基因敲除限制在胶束细胞和其他儿茶酚胺能细胞中。我们发现,TH-Olfr78 KO 小鼠的 HVR 正常。有趣的是,TH-Olfr78 KO 小鼠的神经胶质细胞表现出分子和电生理学改变,分泌囊泡中的多巴胺含量和神经分泌活性也有所降低。这些功能特征与野生型小鼠的 CB 神经母细胞相似。我们认为,尽管Olfr78对CB O2感应并不是必需的,但成熟的神经胶质细胞的表型规格化需要Olfr78依赖途径的激活。
{"title":"Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice","authors":"Olalla Colinas, Peter Mombaerts, J. López-Barneo, Patricia Ortega-Sáenz","doi":"10.1093/function/zqae010","DOIUrl":"https://doi.org/10.1093/function/zqae010","url":null,"abstract":"\u0000 The Olfr78 gene encodes a G-protein coupled receptor that is expressed in olfactory sensory neurons, where it functions as a conventional odorant receptor, and also in several ectopic sites, where its function is not well understood. Olfr78 is one of the most highly expressed mRNA species in glomus cells of the carotid body (CB). These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in Olfr78 knockout mice. In another study, Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. These organismal phenotypes could result from pleiotropic effects of the constitutive Olfr78 knockout mutations in the various CB cell types and/or various organs where this gene is expressed. Therefore, to further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for the phenotypic specification of mature glomus cells.","PeriodicalId":503843,"journal":{"name":"Function","volume":"60 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140439590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-21DOI: 10.1093/function/zqae008
Sunil Nath, Rudi Balling
The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 years since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath's unified theory of energy coupling and ATP synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP consumed, ${Y}_{X/S} ATP$ has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (for example, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs.
沃伯格效应是癌症生物学中一个长期存在的谜团。尽管发现沃伯格效应已经有 100 年之久,相关研究也积累了大量成果,但人们仍无法对最初观察到的癌细胞代谢中的有氧糖酵解现象做出令人信服的生化解释。在这里,我们从化学计量学和电子平衡的原理出发,对这一问题进行了第一原理定量分析。我们使用纳特的能量耦合和 ATP 合成统一理论对结果进行了解释,并从这一新角度对沃伯格及其同事的原始数据进行了分析。结果表明,使用基于 ATP 消耗的生物量产量(${Y}_{X/S} ATP$ )可以很好地模拟沃伯格效应的原始数据,标准偏差值非常小,而且无需使用额外的拟合或可调参数。根据定量分析的结果,提出了一种关于 ATP 和其他关键代谢物(如乳酸)的合成、利用和循环的新型保守机制。该机制为增殖细胞内部和/或之间的代谢共生和耦合提供了新的见解。利用我们的方法获得的基本认识应有助于开发更有效的代谢靶向抗癌药物。
{"title":"The Warburg Effect Reinterpreted, 100 Years on: A First-principles Stoichiometric Analysis, and Interpretation from the Perspective of ATP Metabolism in Cancer Cells","authors":"Sunil Nath, Rudi Balling","doi":"10.1093/function/zqae008","DOIUrl":"https://doi.org/10.1093/function/zqae008","url":null,"abstract":"\u0000 The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 years since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath's unified theory of energy coupling and ATP synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP consumed, ${Y}_{X/S} ATP$ has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (for example, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs.","PeriodicalId":503843,"journal":{"name":"Function","volume":"3 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140443139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-02DOI: 10.1093/function/zqae007
Mohamed Trebak, Khaled Machaca, Patrick G Hogan
{"title":"The Reappraisal of The Reappraisal - CRAC Channels Are Activated by L-Type Ca2+ Channel Blockers, Reply to Bird et al.","authors":"Mohamed Trebak, Khaled Machaca, Patrick G Hogan","doi":"10.1093/function/zqae007","DOIUrl":"https://doi.org/10.1093/function/zqae007","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"16 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139870263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-02DOI: 10.1093/function/zqae007
Mohamed Trebak, Khaled Machaca, Patrick G Hogan
{"title":"The Reappraisal of The Reappraisal - CRAC Channels Are Activated by L-Type Ca2+ Channel Blockers, Reply to Bird et al.","authors":"Mohamed Trebak, Khaled Machaca, Patrick G Hogan","doi":"10.1093/function/zqae007","DOIUrl":"https://doi.org/10.1093/function/zqae007","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"50 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139810377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-27DOI: 10.1093/function/zqae005
Sebastian Edman, Oscar Horwath, Thibaux Van der Stede, Sarah Joan Blackwood, Isabel Moberg, Henrik Strömlind, Fabian Nordström, M. Ekblom, A. Katz, W. Apró, Marcus Moberg
Exercise promotes brain plasticity partly by stimulating increases in mature brain-derived neurotrophic factor (mBDNF), but the role of the pro-BDNF isoform in the regulation of BDNF metabolism in humans is unknown. We quantified the expression of pro-BDNF and mBDNF in human skeletal muscle and plasma at rest, after acute exercise (+/- lactate infusion), and after fasting. Pro-BDNF and mBDNF were analyzed with immunoblotting, ELISA, immunohistochemistry, and qPCR. Pro-BDNF was consistently and clearly detected in skeletal muscle (40-250 pg × mg−1 dry muscle), whereas mBDNF was not. All methods showed a 4-fold greater pro-BDNF expression in type I muscle fibers compared to type II fibers. Exercise resulted in elevated plasma levels of mBDNF (55%) and pro-BDNF (20%), as well as muscle levels of pro-BDNF (∼10%, all P < 0.05). Lactate infusion during exercise-induced a significantly greater increase in plasma mBDNF (115%, P < 0.05) compared to control (saline infusion), with no effect on pro-BDNF levels in plasma or muscle. A 3-day fast resulted in a small increase in plasma pro-BDNF (∼10%, P < 0.05), with no effect on mBDNF. Pro-BDNF is highly expressed in human skeletal muscle, particularly in type I fibers, and is increased after exercise. While exercising with higher lactate augmented levels of plasma mBDNF, exercise-mediated increases in circulating mBDNF likely derives, partly, from release and cleavage of pro-BDNF from skeletal muscle, and partly from neural and other tissues. These findings have implications for pre-clinical and clinical work related to a wide range of neurological disorders such as Alzheimer's, clinical depression, and Amyotrophic lateral sclerosis.
{"title":"Pro-BDNF, but Not Mature BDNF, Is Expressed in Human Skeletal Muscle: Implications for Exercise-Induced Neuroplasticity","authors":"Sebastian Edman, Oscar Horwath, Thibaux Van der Stede, Sarah Joan Blackwood, Isabel Moberg, Henrik Strömlind, Fabian Nordström, M. Ekblom, A. Katz, W. Apró, Marcus Moberg","doi":"10.1093/function/zqae005","DOIUrl":"https://doi.org/10.1093/function/zqae005","url":null,"abstract":"\u0000 Exercise promotes brain plasticity partly by stimulating increases in mature brain-derived neurotrophic factor (mBDNF), but the role of the pro-BDNF isoform in the regulation of BDNF metabolism in humans is unknown. We quantified the expression of pro-BDNF and mBDNF in human skeletal muscle and plasma at rest, after acute exercise (+/- lactate infusion), and after fasting. Pro-BDNF and mBDNF were analyzed with immunoblotting, ELISA, immunohistochemistry, and qPCR.\u0000 Pro-BDNF was consistently and clearly detected in skeletal muscle (40-250 pg × mg−1 dry muscle), whereas mBDNF was not. All methods showed a 4-fold greater pro-BDNF expression in type I muscle fibers compared to type II fibers. Exercise resulted in elevated plasma levels of mBDNF (55%) and pro-BDNF (20%), as well as muscle levels of pro-BDNF (∼10%, all P < 0.05). Lactate infusion during exercise-induced a significantly greater increase in plasma mBDNF (115%, P < 0.05) compared to control (saline infusion), with no effect on pro-BDNF levels in plasma or muscle. A 3-day fast resulted in a small increase in plasma pro-BDNF (∼10%, P < 0.05), with no effect on mBDNF.\u0000 Pro-BDNF is highly expressed in human skeletal muscle, particularly in type I fibers, and is increased after exercise. While exercising with higher lactate augmented levels of plasma mBDNF, exercise-mediated increases in circulating mBDNF likely derives, partly, from release and cleavage of pro-BDNF from skeletal muscle, and partly from neural and other tissues. These findings have implications for pre-clinical and clinical work related to a wide range of neurological disorders such as Alzheimer's, clinical depression, and Amyotrophic lateral sclerosis.","PeriodicalId":503843,"journal":{"name":"Function","volume":"52 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140492151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-19DOI: 10.1093/function/zqae003
Bo Sun, Nia Smith, Alethia J. Dixon, Patrick Osei-Owusu
G protein regulation by regulators of G protein signaling (RGS) proteins of the R4/B family plays a key role in vascular tone maintenance; However, the regulatory mechanisms are poorly understood. Previous studies showed that the loss of Gi/o and Gq/11 regulation by RGS2 and RGS5 is involved in augmented vascular tone and decreased uterine blood flow in mice. RGS2 and 5 are structurally and functionally closely related and are co-expressed in the resistance vasculature, including the uterine vascular bed. However, whether and how RGS2 and 5 coordinate their regulatory activities to finetune G protein signaling and regulate vascular tone are unclear. Here, we tested the hypothesis that the integrated activity of RGS2 and 5 modulates vascular tone by negatively regulating Gi/o signaling to promote cAMP-dependent attenuation of uterine artery (UA) myogenic tone (MT). Using pressure myography, we examined MT of UA segments isolated from non-pregnant wild type (WT), Rgs2−/−, Rgs5−/−, and Rgs2/5 dbKO mice in the absence and presence of exogenous cAMP or chemical inhibition of Gi/o signaling, while nitric oxide tone was continuously suppressed with the eNOS inhibitor, L-NAME. We found that MT was reduced in Rgs5−/− relative to WT or Rgs2−/− UA in the absence or presence of L-NAME. Activating Gi/o with dopamine increased, whereas exogenous cAMP decreased MT in Rgs5−/− UA to similar levels in WT UA. Dual deletion of Rgs2 and 5 abolished the reduction of MT due to the absence of only Rgs5 and enhanced dopamine-induced Gi/o effects in Rgs2/5 dbKO UA. Conversely, and as in WT UA, Gi/o inhibition with pertussis toxin or the application of exogenous cAMP decreased MT in Rgs2/5 dbKO to similar levels in Rgs5−/− UA. Application of the pan-phosphodiesterase (PDE) inhibitor, IBMX, concentration dependently decreased and normalized MT in all genotypes, and blocked dopamine-mediated MT augmentation in Rgs2−/−, Rgs5−/−, and Rgs2/5 dbKO UA. These results indicate that activated Gi/o augments MT by promoting PDE-mediated inhibition of cAMP-dependent vasodilatation; and while both RGS2 and 5 negatively regulate this novel Gi/o-PDE-cAMP signaling pathway, RGS5 dampens the inhibitory efficacy of RGS2 towards Gi/o in uterine arteries.
{"title":"Phosphodiesterases Mediate The Augmentation of Myogenic Constriction by Inhibitory G Protein Signaling And Is Negatively Modulated by The Dual Action of RGS2 And 5","authors":"Bo Sun, Nia Smith, Alethia J. Dixon, Patrick Osei-Owusu","doi":"10.1093/function/zqae003","DOIUrl":"https://doi.org/10.1093/function/zqae003","url":null,"abstract":"\u0000 G protein regulation by regulators of G protein signaling (RGS) proteins of the R4/B family plays a key role in vascular tone maintenance; However, the regulatory mechanisms are poorly understood. Previous studies showed that the loss of Gi/o and Gq/11 regulation by RGS2 and RGS5 is involved in augmented vascular tone and decreased uterine blood flow in mice. RGS2 and 5 are structurally and functionally closely related and are co-expressed in the resistance vasculature, including the uterine vascular bed. However, whether and how RGS2 and 5 coordinate their regulatory activities to finetune G protein signaling and regulate vascular tone are unclear. Here, we tested the hypothesis that the integrated activity of RGS2 and 5 modulates vascular tone by negatively regulating Gi/o signaling to promote cAMP-dependent attenuation of uterine artery (UA) myogenic tone (MT). Using pressure myography, we examined MT of UA segments isolated from non-pregnant wild type (WT), Rgs2−/−, Rgs5−/−, and Rgs2/5 dbKO mice in the absence and presence of exogenous cAMP or chemical inhibition of Gi/o signaling, while nitric oxide tone was continuously suppressed with the eNOS inhibitor, L-NAME. We found that MT was reduced in Rgs5−/− relative to WT or Rgs2−/− UA in the absence or presence of L-NAME. Activating Gi/o with dopamine increased, whereas exogenous cAMP decreased MT in Rgs5−/− UA to similar levels in WT UA. Dual deletion of Rgs2 and 5 abolished the reduction of MT due to the absence of only Rgs5 and enhanced dopamine-induced Gi/o effects in Rgs2/5 dbKO UA. Conversely, and as in WT UA, Gi/o inhibition with pertussis toxin or the application of exogenous cAMP decreased MT in Rgs2/5 dbKO to similar levels in Rgs5−/− UA. Application of the pan-phosphodiesterase (PDE) inhibitor, IBMX, concentration dependently decreased and normalized MT in all genotypes, and blocked dopamine-mediated MT augmentation in Rgs2−/−, Rgs5−/−, and Rgs2/5 dbKO UA. These results indicate that activated Gi/o augments MT by promoting PDE-mediated inhibition of cAMP-dependent vasodilatation; and while both RGS2 and 5 negatively regulate this novel Gi/o-PDE-cAMP signaling pathway, RGS5 dampens the inhibitory efficacy of RGS2 towards Gi/o in uterine arteries.","PeriodicalId":503843,"journal":{"name":"Function","volume":"6 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139525694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}