Exercising with insulin action: the “condition” of skeletal muscle and its influence on the insulin-sensitizing effect of a single bout of exercise

Dorte Enggaard Steenberg

Exercising with insulin action: the “condition” of skeletal muscle and its influence on the insulin-sensitizing effect of a single bout of exercise

Dorte Enggaard Steenberg

Abstract

Det er velkendt, at de gavnlige effekter af fysisk aktivitet medfører en generel øget sundhedstilstand samt bidrager til forebyggelsen og behandlingen af en lang række sygdomme. For eksempel medfører regelmæssig træning øget glykemisk kontrol, hvilket til dels skyldes øget insulinstimuleret glukoseoptagelse i muskler både hos raske og insulinresistente individer. Skeletmuskulaturen er et af de største organer i kroppen og er derfor kvantitativt det vigtigste væv for insulinstimuleret glukoseoptagelse og dermed kroppens regulering af glukosehomeostasen. Ud over effekterne ved regelmæssig træning så er det vist, at også et enkeltsående arbejde øger insulins virkning i de tidligere arbejdende muskler. Dette som følge af en lokal kontraktionsmedieret mekanisme. Dog så er de bagvedliggende molekylære mekanismer for ovenstående fænomen ikke helt klarlagt. Derudover er det stadig uklart, hvilke faktorer der påvirker graden af insulins virkning både i muskler og på helkropsniveau. Derfor er formålet med denne Ph.d. afhandling, at undersøge faktorer der er vigtige for insulins virkning i muskler samt den øgede insulinfølsomhed efter et enkeltstående arbejde. I studie 1 fandt vi, at musklens evne til at øge insulins virkning efter et enkeltstående arbejde var afhængig af musklens træningstilstand med en nedsat evne i den trænede muskel. Dette betyder at øget insulin virkning i musklen som følge af regelmæssig træning, mindsker musklernes evne til at øge insulins virkning yderligere efter et enkeltstående arbejde. Samtidig fandt vi, at arbejdsinducerede fosforylering af TBC1D4 var lavere efter det enkeltstående arbejde formegentlig på grund af en nedsat aktivering af AMPK α2β2γ3. Tilsammen tyder dette på, at AMPK-TBC1D4 signaleringsaksen også spiller en afgørende rolle for den øgede insulinfølsomhed efter et enkeltstående arbejde i mennesker, som det tidligere er blevet vist i gnavere. I studie 2 fandt vi, at virkningen af insulin på helkropsniveau efter et enkeltstående arbejde var afhængig af insulins virkning i de tidligere arbejdende muskler men også de ikke-arbejdende muskler. Et enkeltstående arbejde til udmattelse med en lille muskelgruppe medførte øget insulinfølsomhed i de tidligere arbejdende muskler, men samtidig medførte det også systemiske forandringer, der reducerede insulins virkning i de ikke-arbejdende muskler. På grund af den store mængde inaktiv muskelmasse resulterede det i en nedsat helkrops insulinfølsomhed efter et enkeltstående arbejde. Ved brug af proteomics kunne vi i studie 3 identificere >4000 proteiner i pools af type I og type II muskelfibre taget før og efter en træningsperiode. Denne enorme database vedrørende fiber typer og træningsadaptationer bidrager til forståelse for musklers metabolisme og derudover medfører det mange muligheder for fremtidig forskning. I denne afhandling blev disse data brugt til at undersøge fibertype-specifikke forskelle i kapaciteten for insulinstimuleret glukoseoptagelse i human skeletmuskulatur. På baggrund af dette tyder det ikke på, at kapaciteten for glukosetransport og glykogensyntese er forskellig mellem fibertyper, mens kapaciteten for glukosefosforylering og oxidering ser ud til at være højere i type I fibre. Den træningsinducerede øgede ekspression af proteiner vigtige for insulinstimuleret glukoseoptagelse var ikke forskellig mellem fibertyper. På baggrund af data opnået i studierne kan det konkluderes, at den øgede insulinfølsomhed efter et enkeltstående arbejde afhænger af træningsstatus, mængden af inaktiv vs. aktiv muskel og muligvis også fibertypefordelingen og -rekrutteringen. Resultaterne fra de tre studier vil i afhandlingen blive diskuteret i forhold til den eksisterende litteratur med det formål at identificere faktorer og mekanismer, der har betydning for den øgede insulinfølsomhed efter et enkeltstående arbejde.

Originalsprog	Engelsk

Udgivelsessted	Copenhagen
Forlag	Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
Antal sider	96
Status	Udgivet - 2019

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@phdthesis{24ecdda5850b4f21996fbc4bcbc381b3,

title = "Exercising with insulin action: the “condition” of skeletal muscle and its influence on the insulin-sensitizing effect of a single bout of exercise",

abstract = "The benefits of exercise for the prevention and treatment of various diseases and overall health are well known. For instance, exercise training improves glycemic control in part due to enhanced insulin action on glucose uptake in skeletal muscle of both healthy and insulin resistant individuals. As skeletal muscle is one of the largest tissues in the human body and hence the predominant site forinsulin-stimulated glucose disposal, it is essential for maintaining glucose homeostasis. In addition to the effects of regular exercise training, a single bout of exercise also improves insulin action of the prior exercised muscle due to local contraction-induced mechanisms. However, the underlying molecular mechanisms for this phenomenon are not fully elucidated. Furthermore, factorsdetermining the magnitude of the response to a single bout of exercise on insulin action both within the muscle and at a whole-body level are not completely known. Thus the aim of the present thesis was to investigate factors important for insulin action in muscle and the enhancement of insulin actionby a single bout of exercise.In study 1, we demonstrated that the ability of muscle to enhance insulin action in response to a single bout of exercise is dependent on the training status of the muscle with a lower ability to enhance insulin action in the exercised trained state. This suggest that increased insulin action of the muscle by regular exercise training reduces the ability of a single bout of exercise to enhance insulin actionfurther. The reduced ability to enhance insulin action in response to a single bout of exercise in the trained state was accompanied by a compromised TBC1D4 signaling likely due to a lower activation of AMPK α2β2γ3 during exercise. Thus, our findings in humans also support a role for the AMPKTBC1D4 signaling axis in the insulin-sensitizing effect of a single bout of exercise, as previouslydemonstrated in rodents.In study 2, we demonstrated that whole-body insulin action following a single bout of exercise is dependent of the insulin action in both the prior exercised muscle as well as the non-exercised muscle. As expected, exhaustive exercise of a small muscle group was found to increase insulin action in the prior exercised muscle while, surprisingly, at the same time induce systemic changes that impaired insulin action in non-exercised muscle. Due to the large amount of inactive muscles this resulted in reduced whole-body insulin action after a single bout of exercise. Thus, the magnitude of the response on whole-body insulin action following a single bout of exercise seems to be dependent on the amountof inactive vs. active muscle mass.Lastly, using a proteomic approach we were able to identify >4000 proteins in pools of type I and type II human muscle fibers in study 3. The fibers were obtained before and after a period of endurance exercise training. The fiber type-specific database on adaptations to training provided a unique insight into muscle metabolism, which offers inspiration and possibilities for future research. For the PhD thesis, the database was used to evaluate fiber type-specific differences in the capacity for insulin-stimulated glucose uptake in human skeletal muscle. Based on this, it was suggested that the capacity for glucose transport and glucose incorporation into glycogen was not different between fiber types, whereas the capacity for glucose phosphorylation and oxidation was higher in type I fibers. In response to training, the adaptations important for insulin-stimulated glucose uptake occurred to the same extent between fiber types. In conclusion, the insulin-sensitizing effect of a single bout of exercise is affected by training status, non-exercised vs. exercised muscle mass and perhaps also fiber type composition and recruitment. In the present thesis, results obtained from three studies are discussed in the context of the existing literature with the purpose to elucidate the insulin-sensitizing effect of a single bout of exercise as well as factors and mechanisms contributing to this phenomenon. ",

author = "Steenberg, {Dorte Enggaard}",

note = "CURIS 2019 NEXS 293",

year = "2019",

language = "English",

publisher = "Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen",

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TY - BOOK

T1 - Exercising with insulin action

T2 - the “condition” of skeletal muscle and its influence on the insulin-sensitizing effect of a single bout of exercise

AU - Steenberg, Dorte Enggaard

N1 - CURIS 2019 NEXS 293

PY - 2019

Y1 - 2019

N2 - The benefits of exercise for the prevention and treatment of various diseases and overall health are well known. For instance, exercise training improves glycemic control in part due to enhanced insulin action on glucose uptake in skeletal muscle of both healthy and insulin resistant individuals. As skeletal muscle is one of the largest tissues in the human body and hence the predominant site forinsulin-stimulated glucose disposal, it is essential for maintaining glucose homeostasis. In addition to the effects of regular exercise training, a single bout of exercise also improves insulin action of the prior exercised muscle due to local contraction-induced mechanisms. However, the underlying molecular mechanisms for this phenomenon are not fully elucidated. Furthermore, factorsdetermining the magnitude of the response to a single bout of exercise on insulin action both within the muscle and at a whole-body level are not completely known. Thus the aim of the present thesis was to investigate factors important for insulin action in muscle and the enhancement of insulin actionby a single bout of exercise.In study 1, we demonstrated that the ability of muscle to enhance insulin action in response to a single bout of exercise is dependent on the training status of the muscle with a lower ability to enhance insulin action in the exercised trained state. This suggest that increased insulin action of the muscle by regular exercise training reduces the ability of a single bout of exercise to enhance insulin actionfurther. The reduced ability to enhance insulin action in response to a single bout of exercise in the trained state was accompanied by a compromised TBC1D4 signaling likely due to a lower activation of AMPK α2β2γ3 during exercise. Thus, our findings in humans also support a role for the AMPKTBC1D4 signaling axis in the insulin-sensitizing effect of a single bout of exercise, as previouslydemonstrated in rodents.In study 2, we demonstrated that whole-body insulin action following a single bout of exercise is dependent of the insulin action in both the prior exercised muscle as well as the non-exercised muscle. As expected, exhaustive exercise of a small muscle group was found to increase insulin action in the prior exercised muscle while, surprisingly, at the same time induce systemic changes that impaired insulin action in non-exercised muscle. Due to the large amount of inactive muscles this resulted in reduced whole-body insulin action after a single bout of exercise. Thus, the magnitude of the response on whole-body insulin action following a single bout of exercise seems to be dependent on the amountof inactive vs. active muscle mass.Lastly, using a proteomic approach we were able to identify >4000 proteins in pools of type I and type II human muscle fibers in study 3. The fibers were obtained before and after a period of endurance exercise training. The fiber type-specific database on adaptations to training provided a unique insight into muscle metabolism, which offers inspiration and possibilities for future research. For the PhD thesis, the database was used to evaluate fiber type-specific differences in the capacity for insulin-stimulated glucose uptake in human skeletal muscle. Based on this, it was suggested that the capacity for glucose transport and glucose incorporation into glycogen was not different between fiber types, whereas the capacity for glucose phosphorylation and oxidation was higher in type I fibers. In response to training, the adaptations important for insulin-stimulated glucose uptake occurred to the same extent between fiber types. In conclusion, the insulin-sensitizing effect of a single bout of exercise is affected by training status, non-exercised vs. exercised muscle mass and perhaps also fiber type composition and recruitment. In the present thesis, results obtained from three studies are discussed in the context of the existing literature with the purpose to elucidate the insulin-sensitizing effect of a single bout of exercise as well as factors and mechanisms contributing to this phenomenon.

AB - The benefits of exercise for the prevention and treatment of various diseases and overall health are well known. For instance, exercise training improves glycemic control in part due to enhanced insulin action on glucose uptake in skeletal muscle of both healthy and insulin resistant individuals. As skeletal muscle is one of the largest tissues in the human body and hence the predominant site forinsulin-stimulated glucose disposal, it is essential for maintaining glucose homeostasis. In addition to the effects of regular exercise training, a single bout of exercise also improves insulin action of the prior exercised muscle due to local contraction-induced mechanisms. However, the underlying molecular mechanisms for this phenomenon are not fully elucidated. Furthermore, factorsdetermining the magnitude of the response to a single bout of exercise on insulin action both within the muscle and at a whole-body level are not completely known. Thus the aim of the present thesis was to investigate factors important for insulin action in muscle and the enhancement of insulin actionby a single bout of exercise.In study 1, we demonstrated that the ability of muscle to enhance insulin action in response to a single bout of exercise is dependent on the training status of the muscle with a lower ability to enhance insulin action in the exercised trained state. This suggest that increased insulin action of the muscle by regular exercise training reduces the ability of a single bout of exercise to enhance insulin actionfurther. The reduced ability to enhance insulin action in response to a single bout of exercise in the trained state was accompanied by a compromised TBC1D4 signaling likely due to a lower activation of AMPK α2β2γ3 during exercise. Thus, our findings in humans also support a role for the AMPKTBC1D4 signaling axis in the insulin-sensitizing effect of a single bout of exercise, as previouslydemonstrated in rodents.In study 2, we demonstrated that whole-body insulin action following a single bout of exercise is dependent of the insulin action in both the prior exercised muscle as well as the non-exercised muscle. As expected, exhaustive exercise of a small muscle group was found to increase insulin action in the prior exercised muscle while, surprisingly, at the same time induce systemic changes that impaired insulin action in non-exercised muscle. Due to the large amount of inactive muscles this resulted in reduced whole-body insulin action after a single bout of exercise. Thus, the magnitude of the response on whole-body insulin action following a single bout of exercise seems to be dependent on the amountof inactive vs. active muscle mass.Lastly, using a proteomic approach we were able to identify >4000 proteins in pools of type I and type II human muscle fibers in study 3. The fibers were obtained before and after a period of endurance exercise training. The fiber type-specific database on adaptations to training provided a unique insight into muscle metabolism, which offers inspiration and possibilities for future research. For the PhD thesis, the database was used to evaluate fiber type-specific differences in the capacity for insulin-stimulated glucose uptake in human skeletal muscle. Based on this, it was suggested that the capacity for glucose transport and glucose incorporation into glycogen was not different between fiber types, whereas the capacity for glucose phosphorylation and oxidation was higher in type I fibers. In response to training, the adaptations important for insulin-stimulated glucose uptake occurred to the same extent between fiber types. In conclusion, the insulin-sensitizing effect of a single bout of exercise is affected by training status, non-exercised vs. exercised muscle mass and perhaps also fiber type composition and recruitment. In the present thesis, results obtained from three studies are discussed in the context of the existing literature with the purpose to elucidate the insulin-sensitizing effect of a single bout of exercise as well as factors and mechanisms contributing to this phenomenon.

UR - https://rex.kb.dk/permalink/f/h35n6k/KGL01012069450

M3 - Ph.D. thesis

BT - Exercising with insulin action

PB - Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen

CY - Copenhagen

ER -

Exercising with insulin action: the “condition” of skeletal muscle and its influence on the insulin-sensitizing effect of a single bout of exercise

Abstract

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