American journal of physiology. Cell physiology最新文献

{"title":"Purinergic agonists increase [Ca²⁺]_i in rat conjunctival goblet cells through ryanodine receptor type 3.","authors":"Haakon K Fjaervoll, Ketil A Fjaervoll, Menglu Yang, Ole K Reiten, Jeffrey Bair, Changrim Lee, Tor P Utheim, Darlene Dartt","doi":"10.1152/ajpcell.00291.2024","DOIUrl":"10.1152/ajpcell.00291.2024","url":null,"abstract":"<p><p>ATP and benzoylbenzoyl-ATP (BzATP) increase free cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in conjunctival goblet cells (CGCs) resulting in mucin secretion. The purpose of this study was to investigate the source of the Ca²⁺_i mobilized by ATP and BzATP. First-passage cultured rat CGCs were incubated with Fura-2/AM, and [Ca²⁺]_i was measured under several conditions with ATP and BzATP stimulation. The following conditions were used: <i>1</i>) preincubation with the Ca²⁺ chelator EGTA, <i>2</i>) preincubation with the SERCA inhibitor thapsigargin (10^-6 M), which depletes ER Ca²⁺ stores, <i>3</i>) preincubation with phospholipase C (PLC) or protein kinase A (PKA) inhibitor, or <i>4</i>) preincubation with the voltage-gated calcium channel antagonist nifedipine (10^-5 M) and the ryanodine receptor (RyR) antagonist dantrolene (10^-5 M). Immunofluorescence microscopy (IF) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to investigate RyR presence in rat and human CGCs. ATP-stimulated peak [Ca²⁺]_i was significantly lower after chelating Ca²⁺_i with 2 mM EGTA in Ca²⁺-free buffer. The peak [Ca²⁺]_i increase in CGCs preincubated with thapsigargin, the PKA inhibitor H89, nifedipine, and dantrolene, but not the PLC inhibitor, was reduced for ATP at 10^-5 M and BzATP at 10^-4 M. Incubating CGCs with dantrolene alone decreased [Ca²⁺]_i and induced CGC cell death at a high concentration. RyR3 was detected in rat and human CGCs with IF and RT-qPCR. We conclude that ATP- and BzATP-induced Ca²⁺_i increases originate from the ER and that RyR3 may be an essential regulator of CGC [Ca²⁺]_i. This study contributes to the understanding of diseases arising from defective Ca²⁺ signaling in nonexcitable cells.<b>NEW & NOTEWORTHY</b> ATP and benzoylbenzoyl-ATP (BzATP) induce mucin secretion through an increase in free cytosolic calcium concentration ([Ca²⁺]_i) in conjunctival goblet cells (CGCs). The mechanisms through which ATP and BzATP increase [Ca²⁺]_i in CGCs are unclear. Ryanodine receptors (RyRs) are fundamental in [Ca²⁺]_i regulation in excitable cells. Herein, we find that ATP and BzATP increase [Ca²⁺]_i through the activation of protein kinase A, voltage-gated calcium channels, and RyRs, and that RyRs are crucial for nonexcitable CGCs' Ca²⁺_i homeostasis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C830-C843"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The utility-and limitations-of the rodent synergist ablation model in examining mechanisms of skeletal muscle hypertrophy.","authors":"Michael D Roberts, Troy A Hornberger, Stuart M Phillips","doi":"10.1152/ajpcell.00405.2024","DOIUrl":"10.1152/ajpcell.00405.2024","url":null,"abstract":"<p><p>In this issue, Burke et al. discuss the utility of the rodent synergist ablation (SA) model for examining mechanisms associated with skeletal muscle hypertrophy. In this invited perspective, we aim to complement their original perspective by discussing limitations to the model along with alternative mechanical overload models that have strengths and limitations.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C607-C613"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A positively charged residue at the Kv1.1 T1 interface is critical for voltage-dependent activation and gating kinetics.","authors":"Sonia Majed Hasan, Nawal Aswad, Suleiman Al-Sabah","doi":"10.1152/ajpcell.00422.2024","DOIUrl":"10.1152/ajpcell.00422.2024","url":null,"abstract":"<p><p>Within the tetramerization domain (T1) of most voltage-gated potassium channels (Kv) are highly conserved charged residues that line the T1-T1 interface. We investigated the Kv1.1 residue R86 located at the narrowest region of the T1 interface. A Kv1.1 R86Q mutation was reported in a child diagnosed with lower limb dyskinesia (Set KK, Ghosh D, Huq AHM, Luat AF. <i>Mov Disord Clin Pract</i> 4: 784-786, 2017). The child did not present with episodic ataxia 1 (EA1) symptoms typically associated with Kv1.1 loss-of-function mutations. We characterized the electrophysiological outcome of the R86Q substitution by expressing Kv1.1 in <i>Xenopus laevis</i> oocytes. Mutated α-subunits were able to form functional channels that pass delayed rectifier currents. Oocytes that expressed only mutated α-subunits produced a significant reduction in Kv1.1 current and showed a positive shift in voltage dependence of activation. In addition, there was substantially slower activation and faster deactivation implying a reduction in the time the channel is in its open state. Oocytes co-injected with both mutated and wild-type cRNA in equal amounts, to mimic the heterozygous condition of the disease, showed a decrease in current amplitude at -10 mV, a positive shift in activation voltage-dependence and faster deactivation kinetics when compared with the wild-type channel. These findings indicate that T1 plays a role in Kv1.1's voltage-dependent activation and in its kinetics of activation and deactivation.<b>NEW & NOTEWORTHY</b> This is the first Kv1.1 study to characterize the electrophysiological and structural phenotype of a tetramerization (T1) domain mutation. Surprisingly, the mutated α-subunits were able to tetramerize, albeit with different gating kinetics and voltage dependence. This novel finding points to a clear role of T1 in the channel's voltage dependence and gating. Mimicking the heterozygous condition resulted in milder alterations in channel function when compared with previously reported mutations. This is in agreement with the child's milder symptoms.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C790-C797"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.","authors":"Thomas D Cardaci, Brandon N VanderVeen, Alexander R Huss, Brooke M Bullard, Kandy T Velázquez, Norma Frizzell, James A Carson, Robert L Price, E Angela Murphy","doi":"10.1152/ajpcell.00345.2024","DOIUrl":"10.1152/ajpcell.00345.2024","url":null,"abstract":"<p><p>Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (<i>n</i> = 20) were implanted with LLC cells (10⁶) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; <i>P</i> = 0.006) and size (130%; <i>P</i> = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; <i>P</i> = 0.0109) and \"very high\" oil-red O positive (178%; <i>P</i> = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (<i>R</i>² = 0.5294; <i>P</i> < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio: intermyofibrillar (IMF) = 9%, <i>P</i> = 0.046) with decreases in circularity [circularity: subsarcolemmal (SS) = 6%, <i>P</i> = 0.042] or roundness (roundness: whole = 10%, <i>P</i> = 0.033; IMF = 8%, <i>P</i> = 0.038) as well as decreased LD-mitochondria touch (-15%; <i>P</i> = 0.006), contact length (-38%; <i>P</i> = 0.036), and relative contact (86%; <i>P</i> = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (<i>P</i> < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.<b>NEW & NOTEWORTHY</b> We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C684-C697"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of mitochondrial citrate shuttle alleviates metabolic syndromes induced by high-fat diet.","authors":"Jun-Xian Wang, Yan-Yu Zhang, Yu-Cheng Qian, Yi-Fan Qian, An-Hui Jin, Mai Wang, Yuan Luo, Fang Qiao, Mei-Ling Zhang, Li-Qiao Chen, Zhen-Yu Du","doi":"10.1152/ajpcell.00194.2024","DOIUrl":"10.1152/ajpcell.00194.2024","url":null,"abstract":"<p><p>The mitochondrial citrate shuttle, which relies on the solute carrier family 25 member 1 (SLC25A1), plays a pivotal role in transporting citrate from the mitochondria to the cytoplasm. This shuttle supports glycolysis, lipid biosynthesis, and protein acetylation. Previous research has primarily focused on SLC25A1 in pathological models, particularly high-fat diet (HFD)-induced obesity. However, the impact of SLC25A1 inhibition on nutrient metabolism under HFD remains unclear. To address this gap, we used zebrafish (<i>Danio rerio</i>) and Nile tilapia (<i>Oreochromis niloticus</i>) to evaluate the effects of inhibiting Slc25a1. In zebrafish, we administered Slc25a1-specific inhibitors (CTPI-2) for 4 wk, whereas Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibition of the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance. Of note, glucose tolerance was unaffected. Inhibition of Slc25a1 altered hepatic protein acetylation patterns, with decreased cytoplasmic acetylation and increased mitochondrial acetylation. Under HFD conditions, Slc25a1 inhibition promoted fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). In addition, Slc25a1 inhibition triggered acetylation-induced inactivation of Pdhe1α, leading to a reduction in glucose oxidative catabolism. This was accompanied by enhanced glucose uptake and storage in zebrafish livers. Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and enhancing oxidative phosphorylation for energy production. Our findings provide new insights into the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD.<b>NEW & NOTEWORTHY</b> The mitochondrial citrate shuttle is a crucial physiological process for maintaining metabolic homeostasis. In the present study, we found that inhibition of mitochondrial citrate shuttle (Slc25a1) could alleviate metabolic syndromes induced by high-fat diet (HFD) through remodeling hepatic protein acetylation modification. Briefly, Slc25a1 inhibition reduces hepatic triglyceride deposition by deacetylating Cpt1a and reduces glucose oxidative catabolism by acetylating Pdhe1α. Our study provides new insights into the treatment of diet-induced metabolic syndromes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C737-C749"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The rRNA epitranscriptome and myonuclear SNORD landscape in skeletal muscle fibers contributes to ribosome heterogeneity and is altered by a hypertrophic stimulus.","authors":"Minying Cui, Paulo Jannig, Maral Halladjian, Vandré C Figueiredo, Yuan Wen, Ivan J Vechetti, Nicolai Krogh, Baptiste Jude, Sebastian Edman, Johanna Lanner, John McCarthy, Kevin A Murach, Thomas Sejersen, Henrik Nielsen, Ferdinand von Walden","doi":"10.1152/ajpcell.00301.2024","DOIUrl":"10.1152/ajpcell.00301.2024","url":null,"abstract":"<p><p>In cell biology, ribosomal RNA (rRNA) 2'<i>O</i>-methyl (2'-<i>O</i>-Me) is the most prevalent posttranscriptional chemical modification contributing to ribosome heterogeneity. The modification involves a family of small nucleolar RNAs (snoRNAs) and is specified by box C/D snoRNAs (SNORDs). Given the importance of ribosome biogenesis for skeletal muscle growth, we asked if rRNA 2'-<i>O</i>-Me in nascent ribosomes synthesized in response to a growth stimulus is an unrecognized mode of ribosome heterogeneity in muscle. To determine the pattern and dynamics of 2'-<i>O</i>-Me rRNA, we used a sequencing-based profiling method called RiboMeth-seq (RMS). We applied this method to tissue-derived rRNA of skeletal muscle and rRNA specifically from the muscle fiber using an inducible myofiber-specific RiboTag mouse in sedentary and mechanically overloaded conditions. These analyses were complemented by myonuclear-specific small RNA sequencing to profile SNORDs and link the rRNA epitranscriptome to known regulatory elements generated within the muscle fiber. We demonstrate for the first time that mechanical overload of skeletal muscle <i>1</i>) induces decreased 2'-<i>O</i>-Me at a subset of skeletal muscle rRNA and <i>2</i>) alters the SNORD profile in isolated myonuclei. These findings point to a transient diversification of the ribosome pool via 2'-<i>O</i>-Me during growth and adaptation in skeletal muscle. These findings suggest changes in ribosome heterogeneity at the 2'-<i>O</i>-Me level during muscle hypertrophy and lay the foundation for studies investigating the functional implications of these newly identified \"growth-induced\" ribosomes.<b>NEW & NOTEWORTHY</b> Ribosomal RNAs (rRNAs) are posttranscriptionally modified by 2'<i>O</i>-methyl (2'-<i>O</i>-Me). This study applied RiboMeth-seq (RMS) to detect changes in 2'-<i>O</i>-Me levels during skeletal muscle hypertrophy, uncovering transient diversification of the ribosome pool in skeletal muscle fibers. This work implies a role for ribosome heterogeneity in skeletal muscle growth and adaptation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C516-C524"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional upregulation of the <i>myo</i>-inositol biosynthesis pathway is enhanced by NFAT5 in hyperosmotically stressed tilapia cells.","authors":"Jens Hamar, Avner Cnaani, Dietmar Kültz","doi":"10.1152/ajpcell.00187.2024","DOIUrl":"10.1152/ajpcell.00187.2024","url":null,"abstract":"<p><p>Euryhaline fish experience variable osmotic environments requiring physiological adjustments to tolerate elevated salinity. Mozambique tilapia (<i>Oreochromis mossambicus</i>) possess one of the highest salinity tolerance limits of any fish. In tilapia and other euryhaline fish species, the <i>myo</i>-inositol biosynthesis (MIB) pathway enzymes, <i>myo</i>-inositol phosphate synthase (MIPS) and inositol monophosphatase 1 (IMPA1.1), are among the most upregulated mRNAs and proteins indicating the high importance of this pathway for hyperosmotic (HO) stress tolerance. These abundance changes must be precluded by HO perception and signaling mechanism activation to regulate the expression of <i>MIPS</i> and <i>IMPA1.1</i> genes. In previous work using a <i>O. mossambicus</i> cell line (OmB), a reoccurring osmosensitive enhancer element (OSRE1) in both <i>MIPS</i> and <i>IMPA1.1</i> was shown to transcriptionally upregulate these enzymes in response to HO stress. The OSRE1 core consensus (5'-GGAAA-3') matches the core binding sequence of the predominant mammalian HO response transcription factor, nuclear factor of activated T-cells (NFAT5). HO-challenged OmB cells showed an increase in <i>NFAT5</i> mRNA suggesting NFAT5 may contribute to MIB pathway regulation in euryhaline fish. Ectopic expression of wild-type NFAT5 induced an <i>IMPA1.1</i> promoter-driven reporter by 5.1-fold (<i>P</i> < 0.01). Moreover, expression of dominant negative NFAT5 in HO media resulted in a 47% suppression of the reporter signal (<i>P</i> < 0.005). Furthermore, reductions of IMPA1.1 (37-49%) and MIPS (6-37%) mRNA abundance were observed in HO-challenged NFAT5 knockout cells relative to control cells. Collectively, these multiple lines of experimental evidence establish NFAT5 as a tilapia transcription factor contributing to HO-induced activation of the MIB pathway.<b>NEW & NOTEWORTHY</b> In our study, we use a multi-pronged synthetic biology approach to demonstrate that the fish homolog of the predominant mammalian osmotic stress transcription factor nuclear factor of activated T-cells (NFAT5) also contributes to the activation of hyperosmolality inducible genes in cells of extremely euryhaline fish. However, in addition to NFAT5 the presence of other strong osmotically inducible signaling mechanisms is required for full activation of osmoregulated tilapia genes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C545-C556"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate promotes fatty acid oxidation by the tricarboxylic acid cycle and mitochondrial respiration in muscles of obese mice.","authors":"Sol-Yi Park, Su-Ryun Jung, Jong-Yeon Kim, Yong-Woon Kim, Hoon-Ki Sung, So-Young Park, Kyung-Oh Doh, Jin-Ho Koh","doi":"10.1152/ajpcell.00060.2024","DOIUrl":"10.1152/ajpcell.00060.2024","url":null,"abstract":"<p><p>Lower oxidative capacity in skeletal muscles (SKMs) is a prevailing cause of metabolic diseases. Exercise not only enhances the fatty acid oxidation (FAO) capacity of SKMs but also increases lactate levels. Given that lactate may contribute to tricarboxylic acid cycle (TCA) flux and impact monocarboxylate transporter 1 in the SKMs, we hypothesize that lactate can influence glucose and fatty acid (FA) metabolism. To test this hypothesis, we investigated the mechanism underlying lactate-driven FAO regulation in the SKM of mice with diet-induced obesity (DIO). Lactate was administered to DIO mice immediately after exercise for over 3 wk. We found that increased lactate levels enhanced energy expenditure mediated by fat metabolism during exercise recovery and decreased triglyceride levels in DIO mice SKMs. To determine the lactate-specific effects without exercise, we administered lactate to mice on a high-fat diet (HFD) for 8 wk. Similar to our exercise conditions, lactate increased FAO, TCA cycle activity, and mitochondrial respiration in the SKMs of HFD-fed mice. In addition, under sufficient FA conditions, lactate increased uncoupling protein-3 abundance via the NADH-NAD⁺ shuttle. Conversely, ATP synthase abundance decreased in the SKMs of HFD mice. Taken together, our results suggest that lactate amplifies the adaptive increase in FAO capacity mediated by the TCA cycle and mitochondrial respiration in SKMs under sufficient FA abundance.<b>NEW & NOTEWORTHY</b> Lactate administration post-exercise promotes triglyceride content loss in skeletal muscles (SKMs) and reduced body weight. Lactate enhances fatty acid oxidation in the SKMs of high-fat diet (HFD)-fed mice due to enhanced mitochondrial oxygen consumption. In addition, lactate restores the malate-aspartate shuttle, which is reduced by a HFD, and activates the tricarboxylic acid cycle (TCA) cycle in SKMs. Interestingly, supraphysiological lactate facilitates uncoupling protein-3 expression through NADH/NAD⁺, which is enhanced under high-fat levels in SKMs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C619-C633"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicle miR-206 improves chronic binge alcohol mediated decreased myoblast differentiation in SIV-infected female macaques.","authors":"Brianna L Bourgeois, Eden M Gallegos, Danielle E Levitt, Peter J Bergeaux, Patricia E Molina, Liz Simon","doi":"10.1152/ajpcell.00290.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00290.2024","url":null,"abstract":"<p><p>Alcohol misuse in people with HIV (PWH) and chronic binge alcohol (CBA) administration in simian immunodeficiency virus (SIV)-infected macaques are associated with increased physical frailty and impaired functional skeletal muscle mass, respectively. Previous studies by our group demonstrate that muscle-enriched microRNAs (myomiRs) are differentially expressed in skeletal muscle (SKM) from CBA-administered SIV-infected male macaques and their altered expression contributes to impaired differentiation of SKM stem cells, or myoblasts. MicroRNAs can be transported in extracellular vesicles (EVs) to mediate numerous cellular responses through intercellular communication. The current study tested the hypothesis that EV-mediated delivery of miR-206 can ameliorate CBA-mediated decreased myoblast differentiation. Myoblasts were isolated from SKM of female SIV-infected, antiretroviral therapy-treated macaques that received either CBA (2.5g/kg/day, CBA/SIV) or water (VEH/SIV) for 14.5 months. Myotube and myotube derived EV myomiR expression, including miR-206, was lower in the CBA/SIV group. Overexpression of miR-206 decreased histone deacetylase 4 (<i>HDAC4</i>) and paired box 7 (<i>PAX7</i>) expression in myotubes and increased fusion index, a differentiation index, in CBA/SIV-derived myotubes. Similarly, EV-mediated delivery of miR-206 increased both fusion index and myotube density of CBA/SIV-derived myoblasts. These results support the potential therapeutic utility of EVs in delivering myomiRs to improve SKM stem cell differentiation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced cardiovascular physiology in an individual with type 1 diabetes after 10-year ketogenic diet.","authors":"Joseph C Watso, Austin T Robinson, Saiful Anuar Bin Singar, Jens N Cuba, Andrew P Koutnik","doi":"10.1152/ajpcell.00694.2023","DOIUrl":"10.1152/ajpcell.00694.2023","url":null,"abstract":"<p><p>Adults with type 1 diabetes (T1D) have an elevated risk for cardiovascular disease (CVD) compared with the general population. HbA1c is the primary modifiable risk factor for CVD in T1D. Fewer than 1% of patients achieve euglycemia (<5.7% HbA1c). Ketogenic diets (KD; ≤50 g carbohydrate/day) may improve glycemia and downstream vascular dysfunction in T1D by reducing HbA1c and insulin load. However, there are concerns regarding the long-term CVD risk from a KD. Therefore, we compared data collected in a 60-day window in an adult with T1D on exogenous insulin who consumed a KD for 10 years versus normative values in those with T1D (T1D norms). The participant achieved euglycemia with an HbA1c of 5.5%, mean glucose of 98 [5] mg/dL (median [interquartile range]), 90 [11]% time-in-range 70-180 mg/dL (T1D norms: 1st percentile for all), and low insulin requirements of 0.38 ± 0.03 IU/kg/day (T1D norms: 8th percentile). Seated systolic blood pressure (SBP) was 113 mmHg (T1D norms: 18th percentile), while ambulatory awake SBP was 132 ± 15 mmHg (T1D target: <130 mmHg), blood triglycerides were 69 mg/dL (T1D norms: 34th percentile), low-density lipoprotein was 129 mg/dL (T1D norms: 60th percentile), heart rate was 56 beats/min (T1D norms: >1SD below the mean), carotid-femoral pulse wave velocity was 7.17 m/s (T1D norms: lowest quartile of risk), flow-mediated dilation was 12.8% (T1D norms: >1SD above mean), and cardiac vagal baroreflex gain was 23.5 ms/mmHg (T1D norms: >1SD above mean). Finally, there was no indication of left ventricular diastolic dysfunction from echocardiography. Overall, these data demonstrate below-average CVD risk relative to T1D norms despite concerns regarding the long-term impact of a KD on CVD risk.<b>NEW & NOTEWORTHY</b> Adults with type 1 diabetes (T1D) have a 10-fold higher risk for cardiovascular disease (CVD) compared with the general population. We assessed cardiovascular health metrics in an adult with T1D who presented with a euglycemic HbA1c after following a ketogenic diet for the past 10 years. Despite concerns about the ketogenic diet increasing CVD risk, the participant exhibited below-average CVD risk relative to others with T1D when considering all outcomes together.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C446-C461"},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}