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Article ; Online: OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.

Noone, John / O'Gorman, Donal J / Kenny, Helena C

Trends in endocrinology and metabolism: TEM

2022 Volume 33, Issue 10, Page(s) 710–721

Abstract: The mitochondria are double-membrane organelles integral for energy metabolism. Mitochondrial dynamics is regulated by inner and outer mitochondrial membrane (IMM and OMM) proteins, which promote fission and fusion. Optic atrophy 1 (OPA1) regulates IMM ... ...

Abstract	The mitochondria are double-membrane organelles integral for energy metabolism. Mitochondrial dynamics is regulated by inner and outer mitochondrial membrane (IMM and OMM) proteins, which promote fission and fusion. Optic atrophy 1 (OPA1) regulates IMM fusion, prevents apoptosis, and is a key regulator of morphological change in skeletal and cardiac muscle physiology and pathophysiology. OPA1 fuses the inner membranes of adjacent mitochondria, allowing for an increase in oxidative phosphorylation (OXPHOS). Considering the importance of energy metabolism in whole-body physiology, OPA1 and its regulators have been proposed as novel targets for the treatment of skeletal muscle atrophy and heart failure. Here, we review the role and regulation of OPA1 in skeletal muscle and cardiac pathophysiology, epitomizing its critical role in the cell.
MeSH term(s)	GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Dynamics ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/metabolism ; Myocardium/metabolism
Chemical Substances	Mitochondrial Proteins ; GTP Phosphohydrolases (EC 3.6.1.-) ; OPA1 protein, human (EC 3.6.1.-)
Language	English
Publishing date	2022-08-06
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2022.07.003
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Article ; Online: Baseline phenotypes with preserved β-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies.

Sabatini, Silvia / Nolan, John J / O'Donoghue, Grainne / Kennedy, Aileen / Petrie, John / Walker, Mark / O'Gorman, Donal J / Gastaldelli, Amalia

Metabolism: clinical and experimental

2024 Volume 155, Page(s) 155910

Abstract: Background: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on ...

Abstract	Background: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. Methods: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). Results: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and β-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. Conclusions: Individuals with preserved β-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.
MeSH term(s)	Humans ; Weight Loss/physiology ; Insulin-Secreting Cells/physiology ; Insulin-Secreting Cells/metabolism ; Male ; Female ; Insulin/blood ; Middle Aged ; Diabetes Mellitus, Type 2/blood ; Phenotype ; Prospective Studies ; Blood Glucose/metabolism ; Blood Glucose/analysis ; Adult ; Insulin Resistance/physiology ; Glucose Tolerance Test ; Glucose Intolerance ; Insulin Secretion ; Life Style ; Aged
Chemical Substances	Insulin ; Blood Glucose
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Randomized Controlled Trial
ZDB-ID	80230-x
ISSN	1532-8600 ; 0026-0495
ISSN (online)	1532-8600
ISSN	0026-0495
DOI	10.1016/j.metabol.2024.155910
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Article ; Online: SIRT4 is a regulator of human skeletal muscle fatty acid metabolism influencing inner and outer mitochondrial membrane-mediated fusion.

Noone, John / Rochfort, Keith D / O'Sullivan, Finbarr / O'Gorman, Donal J

Cellular signalling

2023 Volume 112, Page(s) 110931

Abstract: Objective: The mitochondrial phenotype, governed by the balance of fusion-fission, is a key determinant of energy metabolism. The inner and outer mitochondrial membrane (IMM) fusion proteins optic atrophy 1 (OPA1) and Mitofusin 1 and 2 (Mfn1/2) play an ... ...

Abstract	Objective: The mitochondrial phenotype, governed by the balance of fusion-fission, is a key determinant of energy metabolism. The inner and outer mitochondrial membrane (IMM) fusion proteins optic atrophy 1 (OPA1) and Mitofusin 1 and 2 (Mfn1/2) play an important role in this process. Recent evidence also shows that Sirtuin 4 (SIRT4), located within the mitochondria, is involved in the regulation of fatty acid oxidation. The purpose of this study was to determine if SIRT4 expression regulates inner and outer mitochondrial-mediated fusion and substrate utilization within differentiated human skeletal muscle cells (HSkMC). Material and methods: SIRT4 expression was knocked down using small interfering RNA (siRNA) transfection in differentiated HSkMC. Following knockdown, mitochondrial respiration was determined by high-resolution respirometry (HRR) using the Oroboros Oxygraph O2k. Live cell confocal microscopy, quantified using the Mitochondrial Network Analysis (MiNA) toolset, was used to examine mitochondrial morphological change. This was further examined through the measurement of key metabolic and mitochondrial morphological regulators (mRNA and protein) induced by knockdown. Results: SIRT4 knockdown resulted in a significant decrease in LEAK respiration, potentially explained by a decrease in ANT1 protein expression. Knockdown further increased oxidative phosphorylation and protein expression of key regulators of fatty acid metabolism. Quantitative analysis of live confocal imaging of fluorescently labelled mitochondria following SIRT4 knockdown supported the role SIRT4 plays in the regulation of mitochondrial morphology, as emphasized by an increase in mitochondrial network branches and junctions. Measurement of key regulators of mitochondrial dynamics illustrated a significant increase in mitochondrial fusion proteins Mfn1, OPA1 respectively, indicative of an increase in mitochondrial size. Conclusions: This study provides evidence of a direct relationship between the mitochondrial phenotype and substrate oxidation in HSkMC. We identify SIRT4 as a key protagonist of energy metabolism via its regulation of IMM and OMM fusion proteins, OPA1 and Mfn1. SIRT4 knockdown increases mitochondrial capacity to oxidize fatty acids, decreasing LEAK respiration and further increasing mitochondrial elongation via its regulation of mitochondrial fusion.
MeSH term(s)	Humans ; Mitochondrial Membranes/metabolism ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; Energy Metabolism ; Mitochondrial Proteins/metabolism ; Mitochondrial Dynamics ; Fatty Acids/metabolism ; Sirtuins/metabolism
Chemical Substances	Mitochondrial Proteins ; Fatty Acids ; SIRT4 protein, human (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2023-10-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2023.110931
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Article: Data on Determinants Are Needed to Curb the Sedentary Epidemic in Europe. Lessons Learnt from the DEDIPAC European Knowledge Hub

De Craemer, Marieke / Chastin, Sebastien / Ahrens, Wolfgang / Cardon, Greet / Dargent-Molina, Patricia / O'Gorman, Donal / Pigeot, Iris / Mueller-Stierlin, Annabel Sandra / Van Cauwenberg, Jelle

International journal of environmental research and public health, 15(7): 1406

2018

Abstract: Societal and technological changes have resulted in sitting being the dominant posture during most activities of daily living, such as learning, working, travelling and leisure time. Too much time spent in seated activities, referred to as sedentary ... ...

Institution	Leibniz-Institut für Präventionsforschung und Epidemiologie
Abstract	Societal and technological changes have resulted in sitting being the dominant posture during most activities of daily living, such as learning, working, travelling and leisure time. Too much time spent in seated activities, referred to as sedentary behaviour, is a novel concern for public health as it is one of the key lifestyle causes of poor health. The European DEDIPAC (Determinants of Diet and Physical Activity) Knowledge Hub coordinated the work of 35 institutions across 12 European member states to investigate the determinants of sedentary behaviour. DEDIPAC reviewed current evidence, set a theoretical framework and harmonised the available epidemiological data. The main results are summarised. The conclusion is that there is a dire lack of data that is exploitable across Europe to inform policy and intervention. There is an urgent need to develop international data collection compliant with FAIR (Findable, Accessible, Interoperable, Re-usable) and standardised surveillance systems for sedentary behaviour.
Keywords	Determinants ; European cohort ; Sedentary behaviour ; Statement
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Fetuin-A as a Potential Biomarker of Metabolic Variability Following 60 Days of Bed Rest.

Ward, Kiera / Mulder, Edwin / Frings-Meuthen, Petra / O'Gorman, Donal J / Cooper, Diane

Frontiers in physiology

2020 Volume 11, Page(s) 573581

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2020-10-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2020.573581
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Article ; Online: Energy expenditure and affect responses to different types of active video game and exercise.

Monedero, Javier / Murphy, Enda E / O'Gorman, Donal J

PloS one

2017 Volume 12, Issue 5, Page(s) e0176213

Abstract: Background: The purpose of this study was to compare entertainment-themed active video game (AVG) and fitness-themed AVG play with traditional exercise to examine the interaction between physiological and psychological responses.: Methods: ... ...

Abstract	Background: The purpose of this study was to compare entertainment-themed active video game (AVG) and fitness-themed AVG play with traditional exercise to examine the interaction between physiological and psychological responses. Methods: Participants (N = 23) were randomly assigned to 30-min of (i) self-selected intensity exercise (SS-EX), (ii) moderate intensity exercise (MOD-EX), (iii) entertainment-themed video game (ET-VG) and (iv) fitness-themed video game (FT-VG). Physiological and psychological outcomes were recorded before, during and after each trial. Results: All trials met the ACSM criteria for moderate or vigorous physical activity. The [Formula: see text] (68.3±13.9%) and rate of energy expenditure (10.3±3.1kcal/min) was significantly higher in the SS-EX trial with lowest values reported for ET-VG (p<0.05). No differences were found in % heart rate reserve between SS-EX and FT-VG (66.9±12.5% and 67.1±6% respectively). The AVG's were significantly more enjoyable than the exercise trials (p<0.05) and the ET-VG resulted in the highest core flow and psychological well-being (p<0.05). Conclusion: AVG's can elicit physiological responses that meet recommended exercise intensities but are more enjoyable than conventional exercise in young inactive adults. While further work is required, this study highlights the importance of examining the interaction between physiological outcomes and psychological states to increase physical activity and reduce sedentary time.
MeSH term(s)	Adult ; Affect/physiology ; Energy Metabolism/physiology ; Exercise/physiology ; Exercise/psychology ; Female ; Humans ; Judgment ; Male ; Perception ; Surveys and Questionnaires ; Time Factors ; Video Games/psychology ; Young Adult
Language	English
Publishing date	2017-05-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Randomized Controlled Trial
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0176213
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Article ; Online: DietSee: An on-hand, portable, strip-type biosensor for lipolysis monitoring via real-time amperometric determination of glycerol in blood.

Degrelle, Séverine A / Delile, Sébastien / Moog, Sophie / Mouisel, Etienne / O'Gorman, Donal / Moro, Cédric / Denechaud, Pierre-Damien / Torre, Cyril

Analytica chimica acta

2021 Volume 1155, Page(s) 338358

Abstract: Glycerol is a clinical biomarker of lipolysis that is mainly produced by adipose tissues. Blood glycerol content increases in pathological conditions such as metabolic and cardiovascular diseases or cancer cachexia, but also in response to energetic ... ...

Abstract	Glycerol is a clinical biomarker of lipolysis that is mainly produced by adipose tissues. Blood glycerol content increases in pathological conditions such as metabolic and cardiovascular diseases or cancer cachexia, but also in response to energetic stress such as physical exercise. Accurate glycerol monitoring is therefore important in a range of healthcare contexts. However, current methods available for the quantification of glycerol are expensive, time-consuming, and require the extraction of plasma from blood, from which blood glycerol content is then extrapolated. Here, we report the development of a new point-of-care glycerometer device, DietSee, based on a strip-type biosensor that enables the quantification of glycerol directly from whole blood in 6 s. The performance of the biosensor was first evaluated using buffer solutions and spiked human and mouse plasma samples, and its response was compared with that of the gold-standard colorimetric method. The results obtained using DietSee correlated strongly with those from the reference method and demonstrated a linear response to glycerol levels across a wide range of concentrations (40-750 μM) that were representative of those in the human body. Next, the biosensor was validated using spiked human blood samples over a range of 30-55% hematocrit; it also demonstrated a strong correlation with reference measurements under these conditions (R
MeSH term(s)	Animals ; Biosensing Techniques ; Colorimetry ; Glycerol ; Lipolysis ; Mice
Chemical Substances	Glycerol (PDC6A3C0OX)
Language	English
Publishing date	2021-02-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1483436-4
ISSN	1873-4324 ; 0003-2670
ISSN (online)	1873-4324
ISSN	0003-2670
DOI	10.1016/j.aca.2021.338358
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Article ; Online: Decreased expression of mitochondrial aminoacyl-tRNA synthetases causes downregulation of OXPHOS subunits in type 2 diabetic muscle.

López-Soldado, Iliana / Torres, Adrian Gabriel / Ventura, Raúl / Martínez-Ruiz, Inma / Díaz-Ramos, Angels / Planet, Evarist / Cooper, Diane / Pazderska, Agnieszka / Wanic, Krzysztof / O'Hanlon, Declan / O'Gorman, Donal J / Carbonell, Teresa / de Pouplana, Lluís Ribas / Nolan, John J / Zorzano, Antonio / Hernández-Alvarez, María Isabel

Redox biology

2023 Volume 61, Page(s) 102630

Abstract: Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is one of the most important tissues involved in maintaining glucose homeostasis and substrate ... ...

Abstract	Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is one of the most important tissues involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2). GSEA analysis from microarray studies revealed the repression of mitochondrial mt-aaRSs independently of age, which was validated by real-time PCR assays. In agreement with this, a reduced expression of several encoding mt-aaRSs was also detected in skeletal muscle from diabetic (db/db) mice but not in obese ob/ob mice. In addition, the expression of the mt-aaRSs proteins most relevant in the synthesis of mitochondrial proteins, threonyl-tRNA, and leucyl-tRNA synthetases (TARS2 and LARS2) were also repressed in muscle from db/db mice. It is likely that these alterations participate in the reduced expression of proteins synthesized in the mitochondria detected in db/db mice. We also document an increased iNOS abundance in mitochondrial-enriched muscle fractions from diabetic mice that may inhibit aminoacylation of TARS2 and LARS2 by nitrosative stress. Our results indicate a reduced expression of mt-aaRSs in skeletal muscle from T2D patients, which may participate in the reduced expression of proteins synthesized in mitochondria. An enhanced mitochondrial iNOS could play a regulatory role in diabetes.
MeSH term(s)	Mice ; Animals ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Down-Regulation ; Amino Acyl-tRNA Synthetases/genetics ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; RNA, Transfer/metabolism
Chemical Substances	Amino Acyl-tRNA Synthetases (EC 6.1.1.-) ; RNA, Transfer (9014-25-9)
Language	English
Publishing date	2023-02-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2023.102630
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Article ; Online: The impact of 60 days of -6° head down tilt bed rest on mitochondrial content, respiration and regulators of mitochondrial dynamics.

Noone, John / Damiot, Anthony / Kenny, Helena / Chery, Isabelle / Zahariev, Alexandre / Normand, Sylvie / Crampes, François / de Glisezinski, Isabelle / Rochfort, Keith D / Laurens, Claire / Bareille, Marie-Pierre / Simon, Chantal / Bergouignan, Audrey / Blanc, Stéphane / O'Gorman, Donal J

The Journal of physiology

2023

Abstract: It is unclear how skeletal muscle metabolism and mitochondrial function adapt to long duration bed rest and whether changes can be prevented by nutritional intervention. The present study aimed (1) to assess the effect of prolonged bed rest on skeletal ... ...

Abstract	It is unclear how skeletal muscle metabolism and mitochondrial function adapt to long duration bed rest and whether changes can be prevented by nutritional intervention. The present study aimed (1) to assess the effect of prolonged bed rest on skeletal muscle mitochondrial function and dynamics and (2) to determine whether micronutrient supplementation would mitigate the adverse metabolic effect of bed rest. Participants were maintained in energy balance throughout 60 days of bed rest with micronutrient supplementation (INT) (body mass index: 23.747 ± 1.877 kg m
Language	English
Publishing date	2023-12-04
Publishing country	England
Document type	Journal Article
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP284734
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Article ; Online: Interactive video game cycling leads to higher energy expenditure and is more enjoyable than conventional exercise in adults.

Monedero, Javier / Lyons, Elizabeth J / O'Gorman, Donal J

PloS one

2015 Volume 10, Issue 3, Page(s) e0118470

Abstract: Background: Despite the widely accepted health benefits of regular physical activity, only a small percentage of the population meets the current recommendations. The reasons include a wide use of technology and a lack of enjoyment while exercising. The ...

Abstract	Background: Despite the widely accepted health benefits of regular physical activity, only a small percentage of the population meets the current recommendations. The reasons include a wide use of technology and a lack of enjoyment while exercising. The purpose of this study was to compare the physiological, perceptual and enjoyment responses between a single bout of (I) conventional cycling and (II) interactive cycling video game at a matched workload. Methods: A cross-sectional study in 34 healthy participants was performed. Initially, participants completed an incremental maximal cycling test to measure peak oxygen uptake and to determine ventilatory threshold. In random order, participants carried out a 30 min interactive cycling trial and a 30 min conventional cycling trial at 55% of peak power output. During the trials, oxygen uptake and energy expenditure were measured by open-circuit spirometry and heart rate was measured by radiotelemetry. RPE and enjoyment were measured every 10 minutes with Borg scale and a modified PACES scale. Results: Interactive cycling resulted in a significantly greater %V̇O2Reserve (68.2% ± 9.2% vs 64.7% ± 8.1%), rate of energy expenditure (505.8±75.2 vs 487.4±81.2 j·kg-1·min-1), and enjoyment (63.4% ± 17 vs 42% ± 13.6), P<0.05. Participants were working at a higher intensity in relation to the individual's ventilatory threshold during the interactive cycling video game trial (M = 11.86, SE = 3.08) than during the Conventional cycling trial (M = 7.55, SE = 3.16, t(33) = -2.69, P<0.05, r = .42). No significant differences were found for heart rate reserve (72.5 ± 10.4 vs 71.4±10.1%) and RPE (13.1 ± 1.8 vs 13.2 ± 1.7). Conclusion: Interactive cycling games can be a valid alternative to conventional exercise as they result in a higher exercise intensity than conventional cycling and a distraction from aversive cognitive and physiological states at and above the ventilatory threshold.
MeSH term(s)	Adolescent ; Adult ; Bicycling/physiology ; Bicycling/psychology ; Cross-Sectional Studies ; Energy Metabolism ; Exercise/physiology ; Exercise/psychology ; Female ; Heart Rate ; Humans ; Male ; Oxygen/metabolism ; Perception ; Physical Exertion ; Random Allocation ; Video Games/psychology ; Young Adult
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Clinical Study ; Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0118470
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