| 1. |
- Ben Amara, Heithem, 1984, et al.
(författare)
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Immunomodulation by biodegradable Mg-implants promotes soft and hard tissues responses in vivo
- 2023
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Ingår i: Scandinavian Society of Biomaterials conference, 21–24 March 2023, Røros, Norway.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Magnesium (Mg)-based degradable implants are an attractive treatment solution for musculoskeletal injuries, avoiding second-stage surgical removal. In multiple clinical applications, the implant is in contact with both the bone and the overlying soft tissue. Although Mg implants are often presented to hold anti-inflammatory properties, less attention has been paid to the sequential response to these implants including initial immune response and subsequent tissue repair. The present study investigated the molecular, cellular, and structural events taking place at the Mg implant interface to soft tissue and bone after in vivo implantation in dedicated experimental rat models. METHODS: Male Sprague Dawley rats received disc-shaped implants in the dorsum subcutis or screw-shaped implants in the proximal tibial metaphysis. Implants were manufactured from pure magnesium (99.99% - high purity; Mg) or from pure titanium (grade 4; Ti) as control. Animals were euthanized after 1, 3, 6, 14, and 28 day of soft tissue implantation, and after 3 and 28 days of bone implantation. Two types of samples were collected: 1-Implants with the adherent cells (n=7-8/group/time-point). These were allocated for cell counting and /or gene expression analyses of implant-adherent cells. 2-Peri-implant tissue with implants (n = 8/group/time-point). These enabled histological and histomorphometric analyses of the fibrous capsule organization around implants inserted in soft tissues and of osseointegration parameters at the bone-implant interface. Statistical comparisons between experimental groups were run using Kruskal-Wallis, and Mann-Whitney tests (p<0.05). RESULTS: Cells adherent to the surface of the implants featured different gene regulation patterns between Mg and Ti groups (Fig. 1). Consistently in soft tissue and in bone, macrophage polarization markers indicated higher expression of proinflammatory macrophage gene inducible nitric oxide synthase (iNos) initially at Mg versus Ti (3 d in bone and 1-6 d in soft tissue). Afterward, gene expression of both macrophage subtypes markers (proinflammatory – iNos and prohealing – Mannose receptor c1; Mrc1) was comparable between implants, irrespective of their insertion site. Histomorphometry evidenced superior bone-implant contact (at 28 d in bone) and thinner fibrous capsule (at 6-28 d in soft tissue) for Mg versus Ti. CONCLUSIONS: In comparison to non-degradable Ti, both soft tissue and bone responses to biodegradable Mg featured an initial yet transient gene activation of the macrophage proinflammatory subtype. Such immunomodulation by Mg resulted in the reduction of fibrous encapsulation in soft tissue and in the promotion of bone formation at the bone-implant interface. ACKNOWLEDGEMENTS: Mg implants were generously provided by Helmholtz-Zentrum Hereon, Geesthacht, Germany. This project is part of the European Training Network within the framework of Horizon 2020 Marie Skłodowska-Curie Action No 811226.
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| 2. |
- Ben Amara, Heithem, 1984, et al.
(författare)
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In vivo interaction between biodegradable magnesium implants and soft tissue Part II: Kinetics of the cellular response at the host-implant interface
- 2021
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Ingår i: 13th Biometal Conference, 23-26 August 2021, Virtual Conference..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Regenerative therapies often engage multiple tissues. Soft tissue complications (e.g. dehiscences and infection) may violate successful bone regeneration. Magnesium (Mg)-based degradable implants is a promising treatment alternative for musculoskeletal injuries, avoiding second-stage surgical removal. In several clinical applications, the implant is in contact with both the bone and the overlying soft tissue. Whereas the bone response to Mg implants has been a major research focus, less attention has been paid to the soft tissue response. The present study investigated the spatial and temporal molecular, cellular and structural events taking place at the soft tissue-Mg implant interface after in vivo implantation in an experimental rat model. METHODS: Following approval by the Local Ethical Committee at the University of Gothenburg (Dnr 02437/2018), female Sprague-Dawley rats (n=90) were implanted with discs manufactured from pure magnesium (99.99% - high purity; Mg) or from pure titanium (grade 4; Ti) (herein, employed as a control, possessing biocompatibility properties). Subcutaneous pockets were surgically created in the animal dorsum and were implanted with: 1- Ti; or 2- Mg discs; or 3- left without implants (Sham Ti or Sham Mg). After 1, 3, 6, 14 and 28 days, animals were euthanized, and three types of samples were retrieved: 1-Implants with the adherent cells (n=8/group/time-point): for cell counting and molecular gene expression of the implant-adherent cells. 2-Peri-implant exudate (n=8/group/time-point): for analyses of the number, type, viability, and gene expression of cells in the peri-implant space. 3-Peri-implant tissue with implants (n=8/group/time-point): enabling histological and histomorphometric analyses of soft tissue and fibrous capsule organization around the implant. Statistical comparisons were made between experimental groups at each time point and between time-points for each experimental group. (Kruskal-Wallis, Mann-Whitney and Wilcoxon signed-rank tests; p<0.05). RESULTS: Cells recruited to the exudates and adherent to the surface of the implants featured different kinetics between Mg and Ti groups. At the surface of Mg implant, the number of adherent cells sharply increased from 1 day to reach a peak at 6 days, thereafter decreasing toward 28 days. The ratio of implant-adherent/exudate cells was significantly higher at Mg vs Ti after 6 days, whereas the reverse was detected after 28 days. RNA extracted from cells from the different compartments revealed good quality, allowing detailed molecular analysis. After 28d, the fibrous capsule around Mg implants was significantly thinner than around Ti. CONCLUSIONS: In comparison to non-degradable Ti controls, soft tissue healing around biodegradable Mg implants is characterized by an early, intense, but yet transient, cellular influx in the immediate vicinity of the implant surface, and, at later stage, with a reduced fibrotic encapsulation. ACKNOWLEDGEMENTS: Mg implants were generously provided by the Helmholtz-Zentrum Hereon, Geesthacht, Germany. This project is part of the European Training Network within the framework of Horizon 2020 Marie Skodowska-Curie Action No 811226.
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| 3. |
- Ben Amara, Heithem, 1984, et al.
(författare)
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Magnesium implant degradation provides immunomodulatory and proangiogenic effects and attenuates peri-implant fibrosis in soft tissues
- 2023
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Ingår i: Bioactive Materials. - : Elsevier BV. - 2452-199X. ; 26, s. 353-369
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Tidskriftsartikel (refereegranskat)abstract
- Implants made of magnesium (Mg) are increasingly employed in patients to achieve osteosynthesis while degrading in situ. Since Mg implants and Mg2+ have been suggested to possess anti-inflammatory properties, the clinically observed soft tissue inflammation around Mg implants is enigmatic. Here, using a rat soft tissue model and a 1-28 d observation period, we determined the temporo-spatial cell distribution and behavior in relation to sequential changes of pure Mg implant surface properties and Mg2+ release. Compared to nondegradable titanium (Ti) implants, Mg degradation exacerbated initial inflammation. Release of Mg degradation products at the tissue-implant interface, culminating at 3 d, actively initiated chemotaxis and upregulated mRNA and protein immunomodulatory markers, particularly inducible nitric oxide synthase and toll-like receptor-4 up to 6 d, yet without a cytotoxic effect. Increased vascularization was demonstrated morphologically, preceded by high expression of vascular endothelial growth factor. The transition to appropriate tissue repair coincided with implant surface enrichment of Ca and P and reduced peri-implant Mg2+ concentration. Mg implants revealed a thinner fibrous encapsulation compared with Ti. The detailed understanding of the relationship between Mg material properties and the spatial and time-resolved cellular processes provides a basis for the interpretation of clinical observations and future tailoring of Mg implants.
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| 4. |
- Ben Amara, Heithem, 1984, et al.
(författare)
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Promoting soft and hard tissue repair via immunomodulation by the surface degradation of magnesium implants in vivo
- 2023
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Ingår i: Materials for Tomorrow conference by Chalmers University of Technology, 8-10 November 2023, Gothenburg, Sweden.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Magnesium (Mg) is a reactive metallic biomaterial that degrades via surface corrosion upon contact with body fluids. By virtue of its degradation and mechanical properties, Mg implants are currently employed with success to treat musculoskeletal injuries and avoid second-stage surgical removal 1. While these implants are claimed to possess anti-inflammatory properties, this notion contrasts with the initial signs of inflammation observed in the soft tissue of patients treated with Mg implants. This study investigated how the surface degradation of Mg implants in vivo influences the molecular, cellular, and structural events during initial inflammation and subsequent healing of the interfacing soft tissue and bone in comparison to nondegradable titanium (Ti) implants using experimental rat models. METHODS: Rats received disc-shaped implants in their dorsum subcutis or screw-shaped implants in the proximal metaphysis of their tibiae. Implants were manufactured from pure Mg (>99.995% - high purity) or from pure Ti (grade 4). Animals were euthanized after 1, 3, 6, 14, and 28 days of soft tissue implantation, and after 3 and 28 days of bone implantation. Two types of samples were collected: i) Implants only (n = 7-8/group/time-point): for counting and/or gene expression analyses of implant-adherent cells. ii) Implants with peri-implant tissues (n = 5-8/group/time-point): for compositional analysis of the Mg degradation layer in conjunction with the histomorphometry of the fibrous capsule around implants in soft tissues and of osseointegration at the bone–implant interface. Statistical comparisons were run using Kruskal-Wallis and Mann-Whitney tests (p<0.05). RESULTS: Cells adherent to the implant surfaces featured different gene regulation patterns between Mg and Ti groups (Fig. 1). Initially in soft tissue (1–6 d) and bone (3 d), a higher expression of proinflammatory macrophage polarization markers, e.g. inducible nitric oxide synthase (iNos), was shown in Mg versus Ti groups. Afterward, by 28 d, gene expression of both macrophage subtype markers (proinflammatory – iNos, and prohealing – Mannose receptor c1; Mrc1) was comparable between implants, irrespective of their insertion site. Histomorphometry revealed superior bone–implant contact (at 28 d in bone) and thinner fibrous capsule (at 6–28 d in soft tissue) for Mg versus Ti (Fig. 1). The 28 d-degradation layer at the Mg surface was enriched in Ca and P in both soft tissue and bone. CONCLUSIONS: In comparison to Ti implants, both soft tissue and bone responses to Mg implants featured an initial, amplified, yet transient, inflammation marked by the gene activation of the macrophage proinflammatory subtype. Such immunomodulation by the surface degradation of Mg implant promoted more bone deposition, at the bone–implant interface, and less fibrous encapsulation, at the soft tissue–implant interface. REFERENCES: 1. Han et al. Mater Today 2019, 23: 57-71. ACKNOWLEDGEMENTS: Horizon 2020 Marie Skłodowska-Curie Action (No 811226) and Area of Advance Materials/Chalmers and GU Biomaterials. Mg implants were generously provided by Hereon, Geesthacht, Germany.
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| 5. |
- Emanuelsson-Paulson, Therese, 1983-
(författare)
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Polygonal columns in Greek architecture
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis studies the use of polygonal columns in Greek architecture from the Geometric to the Hellenistic period. The main purpose of the research is to study the development, distribution, design, function and use of polygonal columns in order to create a new understanding on how they fit in the development of Greek architecture. The study is based mainly on measurements documented during archeological fieldwork or from excavation reports, and it addresses a critical gap in our current knowledge of Greek architecture since no comparative study focusing on this type of column has previously been conducted.Polygonal or faceted columns have multi-sided shafts with flat sides of equal width. Many polygonal columns were used as status symbols, and so were placed in important monumental buildings. They were also used in combination with fluted columns and could be manufactured from expensive materials such as marble. Polygonal columns were probably cheaper to produce than their fluted counterparts, but expensive compared with the production of functional pillars and supports. The decision to use polygonal rather than round or fluted columns was probably an intentional choice. Furthermore, the development of the polygonal column does not follow the same trajectory of design as that of shafts and capitals on round or fluted columns, and so this design should therefore be studied in its own right.Polygonal columns were used throughout the ancient Greek world. Six groups can be identified on the basis of their shape and design, their functions, geography and chronology. Each group had its own local development in terms of style and use. First, octagonal columns with Doric octagonal capitals from the Peloponnese, the coastal islands and the southern Greek mainland in use from the Geometric to Classical period. Second, octagonal columns with Doric octagonal capitals from Hellenistic Epirus and southern Illyria. Third, Hellenistic octagonal columns with Doric octagonal capitals from other regions. Fourth, eight-sided faceted columns from Greece, Anatolia and the Tauric peninsula during the Archaic to the Hellenistic period. Fifth, Hellenistic 20- and 24-sided polygonal columns with Doric capitals in the Aegean islands and Anatolia. Sixth, polygonal columns with local capitals in Archaic Cyprus. In addition, there is evidence of the use of polygonal columns scattered around towns in the Mediterranean region. In most cases, their design and shape can be connected to one of the main regions mentioned above.Polygonal columns follow the general development of manufacturing techniques in Greek architecture and were used in the same manner as fluted Doric columns. Polygonal shafts were used with Doric capitals in Doric buildings from the Archaic period, but they were never used with other polygonal architectural members. They were, however, sometimes used in combination with capitals from other architectural styles, but since Doric capitals were aesthetically easier to adapt to a polygonal shape, they were usually the preferred choice. Historically, it has been suggested that polygonal columns were a simple precursor to later more complex designs and/or a more economical alternative to fluted columns; these hypotheses are contradicted by the evidence presented in this study. Polygonal columns, with their aesthetically distinctive design, seem instead to be one of the many local variations that were used in Greek architecture.
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| 6. |
- Jolic, Martina, et al.
(författare)
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Leptin receptor gene deficiency minimally affects osseointegration in rats.
- 2023
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Ingår i: Scientific reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic syndrome represents a cluster of conditions such as obesity, hyperglycaemia, dyslipidaemia, and hypertension that can lead to type 2 diabetes mellitus and/or cardiovascular disease. Here, we investigated the influence of obesity and hyperglycaemia on osseointegration using a novel, leptin receptor-deficient animal model, the Lund MetS rat. Machined titanium implants were installed in the tibias of animals with normal leptin receptor (LepR+/+) and those harbouring congenic leptin receptor deficiency (LepR-/-) and were left to heal for 28days. Extensive evaluation of osseointegration was performed using removal torque measurements, X-raymicro-computed tomography, quantitative backscattered electron imaging, Raman spectroscopy, gene expression analysis, qualitative histology, and histomorphometry. Here, we found comparable osseointegration potential at 28days following implant placement in LepR-/- and LepR+/+ rats. However, the low bone volume within the implant threads, higher bone-to-implant contact, and comparable biomechanical stability of the implants point towards changed bone formation and/or remodelling in LepR-/- rats. These findings are corroborated by differences in the carbonate-to-phosphate ratio of native bone measured using Raman spectroscopy. Observations of hypermineralised cartilage islands and increased mineralisation heterogeneity in native bone confirm the delayed skeletal development of LepR-/- rats. Gene expression analyses reveal comparable patterns between LepR-/- and LepR+/+ animals, suggesting that peri-implant bone has reached equilibrium in healing and/or remodelling between the animal groups.
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| 7. |
- Karazisis, Dimitrios, 1977, et al.
(författare)
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The effects of controlled nanotopography, machined topography and their combination on molecular activities, bone formation and biomechanical stability during osseointegration
- 2021
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 136, s. 279-290
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Tidskriftsartikel (refereegranskat)abstract
- The initial cellular and molecular activities at the bone interface of implants with controlled nanoscale topography and microscale roughness have previously been reported. However, the effects of such surface modifications on the development of osseointegration have not yet been determined. This study investigated the molecular events and the histological and biomechanical development of the bone interface in implants with nanoscale topography, microscale roughness or a combination of both. Polished and machined titanium implants with and without controlled nanopatterning (75 nm protrusions) were produced using colloidal lithography and coated with a thin titanium layer to unify the chemistry. The implants were inserted in rat tibiae and subjected to removal torque (RTQ) measurements, molecular analyses and histological analyses after 6, 21 and 28 days. The results showed that nanotopography superimposed on microrough, machined, surfaces promoted an early increase in RTQ and hence produced greater implant stability at 6 and 21 days. Two-way MANOVA revealed that the increased RTQ was influenced by microscale roughness and the combination of nanoscale and microscale topographies. Furthermore, increased bone-implant contact (BIC) was observed with the combined nanopatterned machined surface, although MANOVA results implied that the increased BIC was mainly dependent on microscale roughness. At the molecular level, the nanotopography, per se, and in synergy with microscale roughness, downregulated the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In conclusion, controlled nanotopography superimposed on microrough machined implants promoted implant stability during osseointegration. Nanoscale-driven mechanisms may involve attenuation of the inflammatory response at the titanium implant site. Statement of Significance: The role of combined implant microscale and nanotopography features for osseointegration is incompletely understood. Using colloidal lithography technique, we created an ordered nanotopography pattern superimposed on screwshaped implants with microscale topography. The midterm and late molecular, bone-implant contact and removal torque responses were analysed in vivo. Nanotopography superimposed on microrough, machined, surfaces promoted the implant stability, influenced by microscale topography and the combination of nanoscale and microscale topographies. Increased bone-implant contact was mainly dependent on microscale roughness whereas the nanotopography, per se, and in synergy with microscale roughness, attenuated the proinflammatory tumor necrosis factor alpha (TNF-α) expression. It is concluded that microscale and nanopatterns provide individual as well as synergistic effects on molecular, morphological and biomechanical implant-tissue processes in vivo.
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| 8. |
- Pascual, Didac, et al.
(författare)
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The missing pieces for better future predictions in subarctic ecosystems: A Torneträsk case study
- 2021
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Ingår i: Ambio. - : Springer. - 0044-7447 .- 1654-7209. ; 50:2, s. 375-392
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Forskningsöversikt (refereegranskat)abstract
- Arctic and subarctic ecosystems are experiencing substantial changes in hydrology, vegetation, permafrost conditions, and carbon cycling, in response to climatic change and other anthropogenic drivers, and these changes are likely to continue over this century. The total magnitude of these changes results from multiple interactions among these drivers. Field measurements can address the overall responses to different changing drivers, but are less capable of quantifying the interactions among them. Currently, a comprehensive assessment of the drivers of ecosystem changes, and the magnitude of their direct and indirect impacts on subarctic ecosystems, is missing. The Torneträsk area, in the Swedish subarctic, has an unrivalled history of environmental observation over 100 years, and is one of the most studied sites in the Arctic. In this study, we summarize and rank the drivers of ecosystem change in the Torneträsk area, and propose research priorities identified, by expert assessment, to improve predictions of ecosystem changes. The research priorities identified include understanding impacts on ecosystems brought on by altered frequency and intensity of winter warming events, evapotranspiration rates, rainfall, duration of snow cover and lake-ice, changed soil moisture, and droughts. This case study can help us understand the ongoing ecosystem changes occurring in the Torneträsk area, and contribute to improve predictions of future ecosystem changes at a larger scale. This understanding will provide the basis for the future mitigation and adaptation plans needed in a changing climate.
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| 9. |
- Shah, Furqan A., et al.
(författare)
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Bone without borders - Monetite-based calcium phosphate guides bone formation beyond the skeletal envelope
- 2023
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Ingår i: Bioactive Materials. - : Elsevier BV. - 2452-199X. ; 19, s. 103-114
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Tidskriftsartikel (refereegranskat)abstract
- Calcium phosphates (CaP) represent an important class of osteoconductive and osteoinductive biomaterials. As proof-of-concept, we show how a multi-component CaP formulation (monetite, beta-tricalcium phosphate, and calcium pyrophosphate) guides osteogenesis beyond the physiological envelope. In a sheep model, hollow dome-shaped constructs were placed directly over the occipital bone. At 12 months, large amounts of bone (similar to 75%) occupy the hollow space with strong evidence of ongoing remodelling. Features of both compact bone (osteonal/osteon-like arrangements) and spongy bone (trabeculae separated by marrow cavities) reveal insights into function/need-driven microstructural adaptation. Pores within the CaP also contain both woven bone and vascularised lamellar bone. Osteoclasts actively contribute to CaP degradation/removal. Of the constituent phases, only calcium pyrophosphate persists within osseous (cutting cones) and non-osseous (macrophages) sites. From a translational perspective, this multi-component CaP opens up exciting new avenues for osteotomy-free and minimally-invasive repair of large bone defects and augmentation of the dental alveolar ridge.
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| 10. |
- von Walden, Ferdinand, et al.
(författare)
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Acute endurance exercise stimulates circulating levels of mitochondrial derived peptides in humans
- 2021
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 131:3, s. 1035-1042
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial derived peptides (MDPs) humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis and metabolism. Circulating levels of MDPs are altered in chronic diseases such as diabetes type 2 and chronic kidney disease. Whether acute resistance (RE) or endurance (EE) exercise modulates circulating levels of HN and MOTS-c in humans is unknown. Following familiarization, subjects were randomized to EE (n=10, 45 min cycling at 70% of estimated VO2max), RE (n=10, 4 sets x 7RM, leg press and knee extension), or control (CON, n=10). Skeletal muscle biopsies and blood samples were collected before and at 30 minutes and 3 hours following exercise. Plasma concentration of HN and MOTS-c, skeletal muscle MOTS-c as well as gene expression of exercise related genes were analyzed. Acute EE and RE promoted changes in skeletal muscle gene expression typically seen in response to each exercise modality (c-Myc, 45S pre-rRNA, PGC-1α-total and PGC-1α-ex1b). At rest, circulating levels of HN were positively correlated to MOTS-c levels and age. Plasma levels of MDPs were not correlated to fitness outcomes (VO2max, leg strength or muscle mitochondrial (mt) DNA copy number). Circulating levels of HN were significantly elevated by acute EE but not RE. MOTS-C levels showed a trend to increase after EE. These results indicate that plasma MDP levels are not related to fitness status but that acute EE increases circulating levels of MDPs, in particular HN.
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