scholarly journals Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Alvin Baetiong ◽  
Raúl J. Gazmuri
Keyword(s):  
Adaptive Response ◽  
Glucose Transporter ◽  
Conditional Knockout ◽  
Utilization Efficiency ◽  
Treadmill Running ◽  
Similar Response ◽  
Cyclophilin D ◽  
Session Interaction ◽  
Preferential Utilization ◽  
Β Tubulin

We have previously reported in HEK 293 T cells and in constitutive cyclophilin-D (Cyp-D) knockout (KO) mice that Cyp-D ablation downregulates oxygen consumption (VO2) and triggers an adaptive response that manifest in higher exercise endurance with less VO2. This adaptive response involves a metabolic switch toward preferential utilization of glucose via AMPK-TBC1D1 signaling nexus. We now investigated whether a similar response could be triggered in mice after acute ablation of Cyp-D using tamoxifen-induced ROSA26-Cre-mediated (i.e., conditional KO, CKO) by subjecting them to treadmill exercise involving five running sessions. At their first treadmill running session, CKO mice and controls had comparable VO2 (208.4 ± 17.9 vs. 209.1 ± 16.8 ml/kg min−1), VCO2 (183.6 ± 17.2 vs. 184.8 ± 16.9 ml/kg min−1), and RER (0.88 ± 0.043 vs. 0.88 ± 0.042). With subsequent sessions, CKO mice displayed more prominent reduction in VO2 (genotype & session interaction p = 0.000) with less prominent reduction in VCO2 resulting in significantly increased RER (genotype and session interaction p = 0.013). The increase in RER was consistent with preferential utilization of glucose as respiratory substrate (4.6 ± 0.8 vs. 4.0 ± 0.9 mg/min, p = 0.003). CKO mice also performed a significantly higher treadmill work for given VO2 expressed as a power/VO2 ratio (7.4 ± 0.2 × 10−3 vs. 6.7 ± 0.2 10−3 ratio, p = 0.025). Analysis of CKO skeletal muscle tissue after completion of five treadmill running sessions showed enhanced AMPK activation (0.669 ± 0.06 vs. 0.409 ± 0.11 pAMPK/β-tubulin ratio, p = 0.005) and TBC1D1 inactivation (0.877 ± 0.16 vs. 0.565 ± 0.09 pTBC1D1/β-tubulin ratio, p < 0.05) accompanied by increased glucose transporter-4 levels consistent with activation of the AMPK-TBC1D1 signaling nexus enabling increased glucose utilization. Taken together, our study demonstrates that like constitutive Cyp-D ablation, acute Cyp-D ablation also induces a state of increased O2 utilization efficiency, paving the way for exploring the use of pharmacological approach to elicit the same response, which could be beneficial under O2 limiting conditions.

Abstract 11036: Enhanced Oxygen Utilization Efficiency with Concomitant Activation of the AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knock-Out Mice

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Alvin Baetiong ◽  
Raul J Gazmuri
Keyword(s):  
Adaptive Response ◽  
Glucose Transporter ◽  
Utilization Efficiency ◽  
Treadmill Running ◽  
Similar Response ◽  
Cyclophilin D ◽  
Knock Out ◽  
Session Interaction ◽  
Preferential Utilization ◽  
Β Tubulin

We have previously reported in HEK 293T cells and in constitutive cyclophilin-D (Cyp-D) knock-out (KO) mice that Cyp-D ablation downregulates oxygen consumption (VO 2 ) and triggers an adaptive response that manifests in higher exercise endurance with less VO 2 . This adaptive response involves a metabolic switch toward preferential utilization of glucose via the AMPK-TBC1D1 signaling nexus. We now investigated whether a similar response could be triggered in mice after acute ablation of Cyp-D using conditional KO (CKO) mice by subjecting them to treadmill exercise involving five running sessions. At their first treadmill running session, CKO mice and controls had comparable VO 2 (208.4±17.9 vs 209.1±16.8 ml/kg·min -1 ), VCO 2 (183.6±17.2 vs 184.8±16.9 ml/kg·min -1 ), and RER (0.88±0.043 vs 0.88±0.042). With subsequent sessions, CKO mice displayed more prominent reduction in VO 2 (genotype & session interaction p<0.001) with less prominent reduction in VCO 2 resulting in significantly increased RER (genotype & session interaction p=0.013). The increase in RER was consistent with preferential utilization of glucose as respiratory substrate (4.6±0.8 vs 4.0± 0.9 mg/min, p=0.003). CKO mice also performed a significantly higher treadmill work for given VO 2 expressed as a power/VO 2 ratio (7.4±0.2 x 10 -3 vs 6.7±0.2 10 -3 ratio, p=0.025). Analysis of CKO skeletal muscle tissue after completion of five treadmill running sessions showed enhanced AMPK activation (0.669±0.06 vs 0.409±0.11 pAMPK/β-tubulin ratio, p=0.005) and TBC1D1 inactivation (0.877±0.16 vs 0.565±0.09 pTBC1D1/β-tubulin ratio, p<0.05) accompanied by increased glucose transporter-4 levels consistent with activation of the AMPK-TBC1D1 signaling nexus enabling increased glucose utilization. Taken together, our study demonstrates that like constitutive Cyp-D ablation, acute Cyp-D ablation also induces a state of increased O 2 utilization efficiency, paving the way for exploring the use of a pharmacological approach to elicit the same response, which could be beneficial under O 2 limiting conditions.

Abstract 176: Genetic Ablation of Cyclophilin-D in Mice Increases Physical and Cognitive Performance During Hypoxia

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Alvin Baetiong ◽  
Harrison Kaufman ◽  
Michelle Huynh ◽  
Angela Leschinsky ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Performance ◽  
Exercise Capacity ◽  
Motor Function ◽  
Elevated Plus Maze ◽  
Utilization Efficiency ◽  
Treadmill Running ◽  
Cyclophilin D ◽  
Hypoxic Conditions ◽  
Plus Maze

Introduction: We previously reported that silencing of the mitochondrial peptidyl-prolyl isomerase Cyclophilin-D (Cyp-D) in HEK 293T cells reduces oxygen consumption (VO 2 ). In vivo Cyp-D ablation using constitutive Cyp-D knockout (KO) mice also reduced VO 2 while paradoxically increased exercise endurance, thus demonstrating increased oxygen utilization efficiency. Therefore, we hypothesized that Cyp-D KO mice will display improved physical and cognitive performance during hypoxic conditions. Methods: Two groups of 9 mice each, age and gender-matched, representing wild-type (WT) and Cyp-D KO were subjected to treadmill running first under normobaric normoxic conditions (20.9% O 2 , simulating ground level O 2 levels), and the next day under normobaric hypoxic conditions (8% O 2 simulating 7,600 meters altitude O 2 levels). Total running time and distance, V max , and work performed were measured. A separate set of 9 mice each (Cyp-D KO and WT), were subjected to behavioral assessments; a pole test to assess motor function and an elevated plus-maze test to assess anxiety levels. The tests were conducted first under normoxia and then under hypoxia. Results: Cyp-D KO mice exposed to 8% O 2 displayed increased treadmill work (12±1 vs 8±1 Joules; p =0.02) demonstrating increased exercise capacity, shorter pole-climbing time (21±3 vs 37±4 sec; p =0.006) demonstrating increased agility and cognitive function, and increased elevated plus-maze open arm time (91±31 vs 23±12 sec; p =0.046) demonstrating anti-anxiety like behavior. Conclusions: Cyp-D KO mice demonstrated increased exercise capacity, improved motor function, decreased anxiety, and improved cognitive function under hypoxia. Thus, targeting Cyp-D and modulating its activity may impact several acute and chronic conditions in which oxygen availability is limited. The increased cognitive performance could be helpful when working at low environmental O 2 levels (e.g., high-altitude, underground caves, etc.).

scholarly journals Acute Low-Intensity Treadmill Running Upregulates the Expression of Intestinal Glucose Transporters via GLP-2 in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1735
Author(s):  
Kai Aoki ◽  
Takuji Suzuki ◽  
Fang Hui ◽  
Takuro Nakano ◽  
Koki Yanazawa ◽  
...  
Keyword(s):  
Small Intestine ◽  
Intestinal Tract ◽  
Glucose Transporter ◽  
Treadmill Running ◽  
Low Intensity ◽  
Glucose Transporter 2 ◽  
Intestinal Digestion ◽  
Glucagon Like Peptide ◽  
Low Intensity Exercise ◽  
Carbohydrate Digestion

The effects of exercise on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training increases the expression of molecules involved in carbohydrate digestion and absorption. Exercise was also shown to increase the blood concentration of glucagon-like peptide-2 (GLP-2), which regulates carbohydrate digestion and absorption in the small intestine. Therefore, we investigated the effects of exercise on the expression of molecules involved in intestinal digestion and absorption, including GLP-2. Six-week-old male mice were divided into a sedentary (SED) and low-intensity exercise (LEx) group. LEx mice were required to run on a treadmill (12.5 m/min, 1 h), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest, and plasma, jejunum, ileum, and colon samples were collected, followed by analysis via IHC, EIA, and immunoblotting. The levels of plasma GLP-2 and the jejunum expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter 2 (GLUT2) were higher in LEx mice. Thus, we showed that acute low-intensity exercise affects the expression of molecules involved in intestinal carbohydrate digestion and absorption via GLP-2. Our results suggest that exercise might be beneficial for small intestine function in individuals with intestinal frailty.

scholarly journals Improved exercise capacity in cyclophilin‐D knockout mice associated with enhanced oxygen utilization efficiency and augmented glucose uptake via AMPK‐TBC1D1 signaling nexus

2019 ◽  
Vol 33 (10) ◽  
pp. 11443-11457 ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Alvin Baetiong ◽  
Harrison Kaufman ◽  
Michelle Huynh ◽  
Angela Leschinsky ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Exercise Capacity ◽  
Knockout Mice ◽  
Utilization Efficiency ◽  
Cyclophilin D ◽  
Oxygen Utilization

scholarly journals Hif-1α regulates differentiation of limb bud mesenchyme and joint development

2007 ◽  
Vol 177 (3) ◽  
pp. 451-464 ◽  
Author(s):  
Sylvain Provot ◽  
Dawn Zinyk ◽  
Yasemin Gunes ◽  
Richa Kathri ◽  
Quynh Le ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fetal Development ◽  
Adaptive Response ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Low Oxygen ◽  
Joint Development ◽  
Low Oxygen Tension ◽  
Development And Differentiation

Recent evidence suggests that low oxygen tension (hypoxia) may control fetal development and differentiation. A crucial mediator of the adaptive response of cells to hypoxia is the transcription factor Hif-1α. In this study, we provide evidence that mesenchymal condensations that give origin to endochondral bones are hypoxic during fetal development, and we demonstrate that Hif-1α is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations. To investigate the role of Hif-1α in mesenchymal condensations and in early chondrogenesis, we conditionally inactivated Hif-1α in limb bud mesenchyme using a Prx1 promoter-driven Cre transgenic mouse. Conditional knockout of Hif-1α in limb bud mesenchyme does not impair mesenchyme condensation, but alters the formation of the cartilaginous primordia. Late hypertrophic differentiation is also affected as a result of the delay in early chondrogenesis. In addition, mutant mice show a striking impairment of joint development. Our study demonstrates a crucial, and previously unrecognized, role of Hif-1α in early chondrogenesis and joint formation.

Effect of aging and exercise on GLUT-4 glucose transporters in muscle

1992 ◽  
Vol 263 (2) ◽  
pp. E362-E367 ◽  
Author(s):  
M. Kern ◽  
P. L. Dolan ◽  
R. S. Mazzeo ◽  
J. A. Wells ◽  
G. L. Dohm
Keyword(s):  
Exercise Training ◽  
Glucose Transporter ◽  
Treadmill Running ◽  
Aged Rats ◽  
Middle Aged ◽  
Protein Levels ◽  
Fischer 344 ◽  
Glut 4 ◽  
Significant Difference ◽  
Muscle Types

This study was conducted to investigate whether changes in muscle glucose transporter GLUT-4 protein might be associated with a previously reported deterioration in glucose tolerance with aging, and, furthermore, to determine whether exercise training could increase GLUT-4 protein levels in older animals. GLUT-4 protein concentration was measured in soleus, gastrocnemius, and extensor digitorum longus muscles of trained (10 or 15 wk treadmill running) and untrained young (6-8 mo), middle-aged (15-17 mo), and old (27-29 mo) Fischer 344 rats. All GLUT-4 protein values were expressed as a percent of the mean for the young untrained group. Two-way analysis of variance demonstrated significant main effects of both training and aging in the gastrocnemius and soleus muscles. Exercise training produced significant increases in GLUT-4 protein in the soleus muscle of young (273 +/- 32.9 vs. 100 +/- 38.5%) and middle-aged rats (215 +/- 19.9 vs. 108 +/- 33.2%) compared with sedentary controls. Similar significant increases were also found in the gastrocnemius muscle of young (169 +/- 20.1 vs. 100 +/- 5.8%) and middle-aged rats (167 +/- 46.7 vs. 60 +/- 7.9%) with training. In the oldest rats, GLUT-4 was not significantly increased with training, but the trend toward an increase was apparent in all three muscle types. The main effect of aging was primarily due to a statistically significant difference between the old trained and young trained rats. A trend toward decreased GLUT-4 with aging was apparent in the untrained animals, but this was not statistically significant.

Adaptive response of hypertrophied skeletal muscle to endurance training

1985 ◽  
Vol 59 (1) ◽  
pp. 127-131 ◽  
Author(s):  
M. Riedy ◽  
R. L. Moore ◽  
P. D. Gollnick
Keyword(s):  
Skeletal Muscle ◽  
Training Program ◽  
Endurance Training ◽  
Succinate Dehydrogenase ◽  
Adaptive Response ◽  
Gastrocnemius Muscle ◽  
Treadmill Running ◽  
Glycogen Depletion ◽  
Normal Muscle ◽  
Plantaris Muscle

The response of hypertrophied soleus and plantaris muscle of rats to endurance training was studied. Hypertrophy was produced by bilateral extirpation of the gastrocnemius muscle. A 13-wk training program of treadmill running initiated 30 days after removal of the gastrocnemius muscle accentuated (P less than 0.01) the hypertrophy. Succinate dehydrogenase activities of the enlarged muscles of sedentary rats were similar to those of normal animals, as were the increases associated with training. Phosphorylase and hexokinase activities were unaltered as a result of the experimental perturbations. Rates of glycogen depletion during exercise were lower (P less than 0.01) in the liver and soleus and plantaris muscles of endurance-trained animals. No difference existed in the rate of glycogen depletion of normal and hypertrophied muscle within the sedentary or trained groups. These data demonstrate that extensively hypertrophied muscle responds to training and exercise in a manner similar to that of normal muscle.

GLUT-4 protein and citrate synthase activity in distally or proximally denervated rat soleus muscle

1997 ◽  
Vol 272 (1) ◽  
pp. R429-R432 ◽  
Author(s):  
D. L. Fogt ◽  
M. J. Slentz ◽  
M. E. Tischler ◽  
E. J. Henriksen
Keyword(s):  
Soleus Muscle ◽  
Glucose Transporter ◽  
Citrate Synthase ◽  
Type I ◽  
Similar Response ◽  
Nerve Stump ◽  
Adult Rats ◽  
Protein Levels ◽  
Glut 4 ◽  
Rat Soleus Muscle

The potential role of neurotrophic factors in the decline of glucose transporter (GLUT-4) protein levels and citrate synthase (CS) activity was studied by comparing distally with proximally denervated juvenile rat soleus muscle. Severing of the tibial nerve produced distal (long stump) or proximal (short stump) denervation. GLUT-4 levels and CS activities were measured at 24-h intervals for up to 96 h after denervation. No differences were observed in GLUT-4 or CS activity between soleus muscles left with short or long nerve stumps at any time point. However, within just 24 h, denervation decreased (P < 0.05). GLUT-4 and CS (67.4 +/- 3.3 and 63.4 +/- 1.7% of innervated control values, respectively). Both parameters continued to decline up to 96 h (44.4 +/- 3.1 and 48.7 +/- 4.0%, respectively). There was a significant correlation between the GLUT-4 protein level and CS activity over this 96-h period of denervation (r = 0.653, P < 0.001). A similar response in the 24-h denervated soleus of adult rats was observed. In contrast, 24-h denervation of red gastrocnemius (type IIa fibers) left with a long nerve stump resulted in a prevention of the decline of GLUT-4 and CS seen in red gastrocnemius left with a short nerve stump in both juvenile and adult animals. These results suggest that unlike type IIa muscles, the decline in GLUT-4 level and CS activity in type I soleus muscle after denervation results from a lack of coordinated electrical activity but likely does not involve a neurotrophic agent. These results also support the hypothesis that there is coregulation of decreased expression of GLUT-4 protein and CS activity in this model of reduced neuromuscular activity.

scholarly journals Acute Low-intensity Treadmill Running Induces Intestinal Glucose Transporters via GLP-2 in Mice

2021 ◽  
Author(s):  
Kai Aoki ◽  
Takuji Suzuki ◽  
Fang Hui ◽  
Takuro Nakano ◽  
Koki Yanazawa ◽  
...  
Keyword(s):  
Intestinal Tract ◽  
Glucose Transporter ◽  
Treadmill Running ◽  
Male Mice ◽  
Low Intensity ◽  
Intestinal Digestion ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Low Intensity Exercise ◽  
Carbohydrate Digestion

Exercise affects various organs. However, its effects on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training in-creases the expression of carbohydrate digestion and absorption molecules. Exercise was also shown to increase the concentration of blood glucagon like peptide-2(GLP-2), which regulates carbohydrate digestion and absorption in small intestinal epithelium. Therefore, we investigated the effects of exercise on intestinal digestion and absorption molecules and the levels of GLP-2. 6-wk-old of male mice were divided into 2 groups; sedentary (SED) and low-intensity exercise (LEx). LEx mice were required to run on a treadmill (12.5 m/min, 60 min), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest and plasma, jejunum, ileum, and colon were sampled. Samples were analyzed using EIA and immunoblotting. The levels of plasma GLP-2 and the expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter (GLUT2) in the jejunum were increased in LEx group. We showed that acute low-intensity exer-cise affects the intestinal carbohydrate digestion and absorption molecules via GLP-2. Our results suggest that exercise might provide new benefits to the small intestine for people with intestinal frailty.

HIF1-α-Mediated Gene Expression Induced by Vitamin B1 Deficiency

2013 ◽  
Vol 83 (3) ◽  
pp. 188-197 ◽  
Author(s):  
Rebecca L. Sweet ◽  
Jason A. Zastre
Keyword(s):  
Gene Expression ◽  
Thiamine Deficiency ◽  
Glucose Transporter ◽  
Neuroblastoma Cell ◽  
Hypoxia Inducible Factor ◽  
Clinical Manifestations ◽  
Vitamin B1 ◽  
Low Oxygen ◽  
Glucose Transporter 1 ◽  
Metabolic Intermediates

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

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