| 1. |
- Blackwood, Sarah J, et al.
(författare)
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Extreme Variations in Muscle Fiber Composition Enable Detection of Insulin Resistance and Excessive Insulin Secretion.
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 107:7, s. e2729-e2737
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Muscle fiber composition is associated with peripheral insulin action.OBJECTIVE: We investigated whether extreme differences in muscle fiber composition are associated with alterations in peripheral insulin action and secretion in young, healthy subjects who exhibit normal fasting glycemia and insulinemia.METHODS: Relaxation time following a tetanic contraction was used to identify subjects with a high or low expression of type I muscle fibers: group I (n=11), area occupied by type I muscle fibers = 61.0 ± 11.8%; group II (n=8), type I area = 36.0 ± 4.9% (P<0.001). Biopsies were obtained from the vastus lateralis muscle and analyzed for mitochondrial respiration on permeabilized fibers, muscle fiber composition and capillary density. An intravenous glucose tolerance test was performed and indices of glucose tolerance, insulin sensitivity and secretion were determined.RESULTS: Glucose tolerance was similar between groups, whereas whole-body insulin sensitivity was decreased by ~50% in group II vs group I (P=0.019). First phase insulin release (area under the insulin curve during 10 min after glucose infusion) was increased by almost 4-fold in group II vs I (P=0.01). Whole-body insulin sensitivity was correlated with % area occupied by type I fibers (r=0.54; P=0.018) and capillary density in muscle (r=0.61; P=0.005), but not with mitochondrial respiration. Insulin release was strongly related to % area occupied by type II fibers (r=0.93; P<0.001).CONCLUSIONS: Assessment of muscle contractile function in young healthy subjects may prove useful in identifying individuals with insulin resistance and enhanced glucose stimulated insulin secretion prior to onset of clinical manifestations.
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| 2. |
- Blackwood, Sarah J, et al.
(författare)
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Insulin resistance after a 3-day fast is associated with an increased capacity of skeletal muscle to oxidize lipids.
- 2023
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 324:5, s. E390-E401
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Tidskriftsartikel (refereegranskat)abstract
- There is a debate on whether lipid-mediated insulin resistance derives from an increased or decreased capacity of muscle to oxidize fats. Here we examine the involvement of muscle fiber composition in the metabolic responses to a 3-day fast (starvation, which results in increases in plasma lipids and insulin resistance) in two groups of healthy young subjects: 1, area occupied by type I fibers = 61.0 ± 11.8%; 2, type I area = 36.0 ± 4.9% (P<0.001). Muscle biopsies and intravenous glucose tolerance tests were performed after an overnight fast and after starvation. Biopsies were analyzed for muscle fiber composition and mitochondrial respiration. Indices of glucose tolerance and insulin sensitivity were determined. Glucose tolerance was similar in both groups after an overnight fast and deteriorated to a similar degree in both groups after starvation. In contrast, whole-body insulin sensitivity decreased markedly after starvation in group 1 (P<0.01), whereas the decrease in group 2 was substantially smaller (P=0.06). Non-esterified fatty acids and β-hydroxybutyrate levels in plasma after an overnight fast were similar between groups and increased markedly and comparably in both groups after starvation, demonstrating similar degrees of lipid load. The capacity of permeabilized muscle fibers to oxidize lipids was significantly higher in group 1 vs. 2, whereas there was no significant difference in pyruvate oxidation between groups. The data demonstrate that loss of whole-body insulin sensitivity after short-term starvation is a function of muscle fiber composition and is associated with an elevated rather than a diminished capacity of muscle to oxidize lipids.
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| 3. |
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| 4. |
- Cardinale, Daniele A., 1982-, et al.
(författare)
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Enhanced Skeletal Muscle Oxidative Capacity and Capillary-to-Fiber Ratio Following Moderately Increased Testosterone Exposure in Young Healthy Women
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recently, it was shown that exogenously administered testosterone enhances endurance capacity in women. In this study, our understanding on the effects of exogenous testosterone on key determinants of oxygen transport and utilization in skeletal muscle is expanded.Methods: In a double-blinded, randomized, placebo-controlled trial, 48 healthy active women were randomized to 10 weeks of daily application of 10 mg of testosterone cream or placebo. Before and after the intervention, VO2 max, body composition, total hemoglobin (Hb) mass and blood volumes were assessed. Biopsies from the vastus lateralis muscle were obtained before and after the intervention to assess mitochondrial protein abundance, capillary density, capillary-to-fiber (C/F) ratio, and skeletal muscle oxidative capacity.Results: Maximal oxygen consumption per muscle mass, Hb mass, blood, plasma and red blood cell volumes, capillary density, and the abundance of mitochondrial protein levels (i.e., citrate synthase, complexes I, II, III, IV-subunit 2, IV-subunit 4, and V) were unchanged by the intervention. However, the C/F ratio, specific mitochondrial respiratory flux activating complex I and linked complex I and II, uncoupled respiration and electron transport system capacity, but not leak respiration or fat respiration, were significantly increased following testosterone administration compared to placebo.Conclusion: This study provides novel insights into physiological actions of increased testosterone exposure on key determinants of oxygen diffusion and utilization in skeletal muscle of women. Our findings show that higher skeletal muscle oxidative capacity coupled to higher C/F ratio could be major contributing factors that improve endurance performance following moderately increased testosterone exposure.
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| 5. |
- Cardinale, Daniele A., 1982-, et al.
(författare)
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Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes.
- 2021
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 131:1, s. 388-400
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The maintenance of healthy and functional mitochondria is the result of a complex mitochondrial turnover and herein quality-control program which includes both mitochondrial biogenesis and autophagy of mitochondria. The aim of this study was to examine the effect of an intensified training load on skeletal muscle mitochondrial quality control in relation to changes in mitochondrial oxidative capacity, maximal oxygen consumption and performance in highly trained endurance athletes.METHODS: 27 elite endurance athletes performed high intensity interval exercise followed by moderate intensity continuous exercise 3 days per week for 4 weeks in addition to their usual volume of training. Mitochondrial oxidative capacity, abundance of mitochondrial proteins, markers of autophagy and antioxidant capacity of skeletal muscle were assessed in skeletal muscle biopsies before and after the intensified training period.RESULTS: The intensified training period increased several autophagy markers suggesting an increased turnover of mitochondrial and cytosolic proteins. In permeabilized muscle fibers, mitochondrial respiration was ~20 % lower after training although some markers of mitochondrial density increased by 5-50%, indicative of a reduced mitochondrial quality by the intensified training intervention. The antioxidative proteins UCP3, ANT1, and SOD2 were increased after training, whereas we found an inactivation of aconitase. In agreement with the lower aconitase activity, the amount of mitochondrial LON protease that selectively degrades oxidized aconitase, was doubled.CONCLUSION: Together, this suggests that mitochondrial respiratory function is impaired during the initial recovery from a period of intensified endurance training while mitochondrial quality control is slightly activated in highly trained skeletal muscle.
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| 6. |
- Edman, Sebastian, et al.
(författare)
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Need for speed : Human fast-twitch mitochondria favor power over efficiency
- 2024
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Ingår i: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 79
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Human skeletal muscle consists of a mixture of slow- and fast-twitch fibers with distinct capacities for contraction mechanics, fermentation, and oxidative phosphorylation. While the divergence in mitochondrial volume favoring slow-twitch fibers is well established, data on the fiber type-specific intrinsic mitochondrial function and morphology are highly limited with existing data mainly being generated in animal models. This highlights the need for more human data on the topic.Methods: Here, we utilized THRIFTY, a rapid fiber type identification protocol to detect, sort, and pool fast- and slow-twitch fibers within 6 h of muscle biopsy sampling. Respiration of permeabilized fast- and slow-twitch fiber pools was then analyzed with high-resolution respirometry. Using standardized western blot procedures, muscle fiber pools were subsequently analyzed for control proteins and key proteins related to respiratory capacity.Results: Maximal complex I+II respiration was 25% higher in human slow-twitch fibers compared to fast-twitch fibers. However, per mitochondrial volume, the respiratory rate of mitochondria in fast-twitch fibers was approximately 50% higher for complex I+II, which was primarily mediated through elevated complex II respiration. Furthermore, the abundance of complex II protein and proteins regulating cristae structure were disproportionally elevated in mitochondria of the fast-twitch fibers. The difference in intrinsic respiratory rate was not reflected in fatty acid–or complex I respiration.Conclusion: Mitochondria of human fast-twitch muscle fibers compensate for their lack of volume by substantially elevating intrinsic respiratory rate through increased reliance on complex II.
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| 7. |
- Edman, Sebastian, 1990-
(författare)
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Skeletal muscle fiber types in man : With special reference to anabolic signaling and mitochondrial bioenergetics
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human skeletal muscle consists of a mixture of slow-twitch (type I) and fast-twitch (type II) fibers. The type I fibers are endurance-oriented, with a metabolic system and infrastructure that supports aerobic metabolism. This entails a well-developed capillary grid and a mitochondrial network proportioned to the number of contractile units within the fiber. These fibers generally have slower and less forceful contraction mechanics and more limited muscle growth as a resource-efficient metabolic energy system is prioritized over increasing the number of contractile units. By contrast, type II fibers prioritize contractile capabilities and force generation at the cost of resource efficiency. These fibers have a substantially lower mitochondrial volume but prioritize structures and organelles that benefit muscle contraction instead. It is well known that resistance exercise combined with dietary protein intake stimulates the growth of contractile proteins leading to an increased muscle mass over time. Muscle mass accumulation is primarily driven by the amplification of muscle protein synthesis, which in turn is largely governed by the mTORC1 signaling pathway within the muscle cell. Little is known about how mTORC1 signaling regulates growth in the different fiber types. Furthermore, it is unknown whether blunted anabolic signaling in type II fibers of the elderly may explain why losses of muscle mass occur primarily in these fibers with advancing age.Endurance exercise, on the other hand, primarily stimulates a prioritization to synthesize new mitochondria to support the high demand for sustainable aerobic energy output. However, it remains to be determined if mitochondria created within type I and type II fibers are equal, or whether they have adapted to their respective milieu in any way. Therefore, the aim of the current thesis was to investigate how the mTORC1 pathway in type I and type II fibers responds to resistance exercise and nutritional stimuli in the form of essential amino acids (EAA), and to determine if this response is influenced by age. Fiber type-specific mitochondrial populations, including their respiratory capacity, were also investigated. To facilitate these investigations, a new and improved method for muscle fiber type identification was developed.In paper I, the phosphorylation of mTORC1 in response to resistance exercise and EAA intake was examined in 684 individual muscle fibers. Unsurprisingly, a significant increase in mTORC1 signaling was seen following the combination of resistance exercise and EAA intake, whereas the rise following resistance exercise alone was more modest. However, no evidence of a discrete response in the different fiber types was found. In paper II, a new method was developed to facilitate the work surrounding fiber type-specific muscle physiology by limiting the extreme time requirements of fiber type identification of large sample sets of muscle fibers. The novel method, which was named THRIFTY, allows an experienced technician to classify over 800 fibers in under 11h.Paper III utilizes the high throughput of the THRIFTY method described in paper II to create the most extensive study to date on individually dissected muscle fibers with 27 602 included fibers. Here, the aim was to investigate whether the fiber type-specific muscle atrophy of the type II fibers in aging could be explained by an onset of anabolic resistance in these fibers. For this investigation, ten young and ten elderly men were recruited to perform a unilateral resistance exercise session followed by ingestion of EAA. This paper showed a slightly elevated mTORC1 signaling response in type I fibers. However, there were no signs of blunted mTORC1 signaling in the elderly. In paper IV, the high speed of the THRIFTY method was utilized to analyze the mitochondrial respiratory function of permeabilized type I and type II muscle fibers. In addition, the intrinsic protein expression of mitochondria in the type I and type II muscle fibers was analyzed. As expected, a higher volume of mitochondria and a greater respiratory rate in the type I fibers were found. However, on a per mitochondria basis, a higher maximal respiratory rate was observed in type II fibers together with increased levels of proteins in the electron transport chain. Likewise, proteins regulating mitochondrial fission and fusion were more highly expressed in the type II fiber mitochondria, which may be a compensatory mechanism for the low volume. In conclusion, both fiber types show robust increases in mTORC1 signaling in response to exercise and EAA ingestion. The results indicate that the response is slightly stronger in the type I fibers, which is contrary to what was predicted. Moreover, the highly specific type II fiber atrophy seen with aging cannot be explained by a blunted anabolic response in these fibers. Surprisingly, the mitochondria of type II fibers possess a higher respiratory capacity. However, this discrepancy is concealed by the vast difference in mitochondrial volume favoring type I fibers, ultimately leading to an overall greater respiratory rate in the type I fibers.
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| 8. |
- Flockhart, Mikael, et al.
(författare)
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A simple model for diagnosis of maladaptations to exercise training
- 2022
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Ingår i: Sports Medicine Open. - : Springer. - 2198-9761 .- 2199-1170. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The concept of overreaching and super compensation is widely in use by athletes and coaches seeking to maximize performance and adaptations to exercise training. The physiological aspects of acute fatigue, overreaching and non-functional overreaching are, however, not well understood, and well-defined negative physiological outcomes are missing. Instead, the concept relies heavily on performance outcomes for differentiating between the states. Recent advancements in the field of integrated exercise physiology have associated maladaptations in muscular oxidative function to high loads of exercise training.Method: Eleven female and male subjects that exercised regularly but did not engage in high-intensity interval training (HIIT) were recruited to a 4-week long training intervention where the responses to different training loads were studied. Highly monitored HIIT sessions were performed on a cycle ergometer in a progressive fashion with the intent to accomplish a training overload. Throughout the intervention, physiological and psychological responses to HIIT were assessed, and the results were used to construct a diagnostic model that could indicate maladaptations during excessive training loads.Results: We here use mitochondrial function as an early marker of excessive training loads and show the dynamic responses of several physiological and psychological measurements during different training loads. During HIIT, a loss of mitochondrial function was associated with reduced glycolytic, glucoregulatory and heart rate responses and increased ratings of perceived exertion in relation to several physiological measurements. The profile of mood states was highly affected after excessive training loads, whereas performance staled rather than decreased. By implementing five of the most affected and relevant measured parameters in a diagnostic model, we could successfully, and in all the subjects, identify the training loads that lead to maladaptations.Conclusions: As mitochondrial parameters cannot be assessed without donating a muscle biopsy, this test can be used by coaches and exercise physiologists to monitor adaptation to exercise training for improving performance and optimizing the health benefits of exercise. Clinical trial registry number NCT04753021 . Retrospectively registered 2021-02-12.
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| 9. |
- Flockhart, Mikael, et al.
(författare)
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Continuous Glucose Monitoring in Endurance Athletes : Interpretation and Relevance of Measurements for Improving Performance and Health.
- 2024
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Ingår i: Sports Medicine. - : Springer. - 0112-1642 .- 1179-2035. ; 54:2, s. 247-255
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Tidskriftsartikel (refereegranskat)abstract
- Blood glucose regulation has been studied for well over a century as it is intimately related to metabolic health. Research in glucose transport and uptake has also been substantial within the field of exercise physiology as glucose delivery to the working muscles affects exercise capacity and athletic achievements. However, although exceptions exist, less focus has been on blood glucose as a parameter to optimize training and competition outcomes in athletes with normal glucose control. During the last years, measuring glucose has gained popularity within the sports community and successful endurance athletes have been seen with skin-mounted sensors for continuous glucose monitoring (CGM). The technique offers real-time recording of glucose concentrations in the interstitium, which is assumed to be equivalent to concentrations in the blood. Although continuous measurements of a parameter that is intimately connected to metabolism and health can seem appealing, there is no current consensus on how to interpret measurements within this context. Well-defined approaches to use glucose monitoring to improve endurance athletes' performance and health are lacking. In several studies, blood glucose regulation in endurance athletes has been shown to differ from that in healthy controls. Furthermore, endurance athletes regularly perform demanding training sessions and can be exposed to high or low energy and/or carbohydrate availability, which can affect blood glucose levels and regulation. In this current opinion, we aim to discuss blood glucose regulation in endurance athletes and highlight the existing research on glucose monitoring for performance and health in this population.
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| 10. |
- Flockhart, Mikael, et al.
(författare)
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Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers.
- 2021
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Ingår i: Cell Metabolism. - : Cell Press. - 1550-4131 .- 1932-7420. ; 33:5, s. 957-970
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Tidskriftsartikel (refereegranskat)abstract
- Exercise training positively affects metabolic health through increased mitochondrial oxidative capacity and improved glucose regulation and is the first line of treatment in several metabolic diseases. However, the upper limit of the amount of exercise associated with beneficial therapeutic effects has not been clearly identified. Here, we used a training model with a progressively increasing exercise load during an intervention over 4 weeks. We closely followed changes in glucose tolerance, mitochondrial function and dynamics, physical exercise capacity, and whole-body metabolism. Following the week with the highest exercise load, we found a striking reduction in intrinsic mitochondrial function that coincided with a disturbance in glucose tolerance and insulin secretion. We also assessed continuous blood glucose profiles in world-class endurance athletes and found that they had impaired glucose control compared with a matched control group.
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