Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise

Whitham, Martin; Parker, Benjamin L.; Friedrichsen, Martin; Hingst, Janne R.; Hjorth, Marit; Hughes, William E.; Egan, Casey L.; Cron, Lena; Watt, Kevin I.; Kuchel, Rhiannon P.; Jayasooriah, Navind; Estévez, Emma; Petzold, Tim; Suter, Catherine M.; Gregorevic, Paul; Kiens, Bente; James, David E.; Febbraio, Mark A.

doi:10.1016/j.cmet.2017.12.001

Cited by 434 publications

(469 citation statements)

References 68 publications

Supporting

Mentioning

437

Contrasting

Unclassified

Order By: Relevance

“…In the femoral vein, EVs are increase immediately following 60 min of acute cycle exercise with a return to baseline at 4 h post‐exercise in humans (Whitham et al., ). EVs also increase in the peripheral circulation in response to exercise in humans (Fruhbeis, Helmig, Tug, Simon, & Kramer‐Albers, ; Whitham et al., ). In mice, acute exercise appears to reduce the skeletal muscle intracellular expression of Alix consistent with EXO release (Safdar et al., ).…”

Section: Discussionmentioning

confidence: 99%

Multivesicular body and exosome pathway responses to acute exercise

Garner

Solfest

Nie

et al. 2020

Experimental Physiology

View full text Add to dashboard Cite

New Findings What is the central question of this study?What is the impact of acute aerobic and aerobic + resistance (concurrent) exercise on the regulation of multivesicular body formation in human skeletal muscle? What is the main finding and its importance?Gene expression for proteins associated with multivesicular body biogenesis was increased in response to concurrent exercise, and gene expression of microRNA processing (genetic information) was increased in response to aerobic and concurrent exercise. A greater understanding of the processing of multivesicular bodies in response to acute exercise may lead to novel treatments focused on intercellular communication pathways. Abstract Regular aerobic exercise (AEx) and resistance exercise (REx) promote many beneficial adaptations. Skeletal muscle participates in intercellular communication in part through the release of myokines and extracellular vesicles including exosomes (EXOs), the latter containing mRNA, microRNA (miRNA), lipids and proteins. Exercise‐induced regulation of skeletal muscle multivesicular body (MVB) biogenesis leading to EXO formation and release is poorly understood. We hypothesized that acute exercise would increase skeletal muscle MVB biogenesis and EXO release pathways with a greater response to aerobic + resistance exercise (A+REx) than to AEx alone. Twelve sedentary, healthy male subjects exercised on a cycle ergometer for 45 min (AEx) followed by single leg, knee extensor, resistance exercise (A+REx). Vastus lateralis biopsies were obtained at rest and 1 h post‐exercise. Key components of the MVB biogenesis, EXO biogenesis and release, and miRNA processing pathways were analysed. Clathrin and Alix mRNA (MVB biogenesis) were increased by A+REx, while DICER and exportin mRNA (miRNA processing) were increased by AEx and A+REx. There were positive relationships between MVBs and miRNA processing genes following both AEx and A+REx consistent with coordinated regulation of these interrelated processes (Alix mRNA increased with Drosha, exportin and Dicer mRNA). Acute exercise increases the regulation of components of MVB and EXO pathways as well as miRNA processing components. A greater understanding of the production and packaging of skeletal muscle MVBs, EXOs and mature miRNA could lead to novel treatments focused on intercellular communication.

show abstract

Section: Discussionmentioning

confidence: 99%

Multivesicular body and exosome pathway responses to acute exercise

Garner

Solfest

Nie

et al. 2020

Experimental Physiology

View full text Add to dashboard Cite

show abstract

“…In the femoral venous circulation, exosomes are present and increased in response to aerobic exercise in humans; however, the cell lineage of the exosomes is unknown (Whitham et al, 2018). Exosomes have attracted great interest given their importance for intracellular communication, but little is known concerning the molecular basis of skeletal muscle exosome packaging, transportation and secretion.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle‐derived exosomes regulate endothelial cell functions via reactive oxygen species‐activated nuclear factor‐κB signalling

Nie

Sato

Garner

et al. 2019

Experimental Physiology

View full text Add to dashboard Cite

New Findings What is the central question of this study?Capillary rarefaction is found in diabetic and aged muscle, whereas exercise increases skeletal muscle angiogenesis. The association implies a crosstalk between muscle cells and endothelial cells. The underlying mechanisms mediating the crosstalk between these cells remains to be elucidated fully. What is the main finding and its importance?Endothelial cell functions are regulated by skeletal muscle cell‐derived exosomes via a vascular endothelial growth factor‐independent pathway. This study reveals a new mechanism mediating the crosstalk between skeletal muscle cells and endothelial cells. Abstract Loss of skeletal muscle capillarization, known as capillary rarefaction, is found in type 2 diabetes, chronic heart failure and healthy ageing and is associated with impaired delivery of substrates to the muscle. However, the interaction and communication of skeletal muscle with endothelial cells in the regulation of capillaries surrounding the muscle remains elusive. Exosomes are a type of secreted extracellular vesicle containing mRNAs, proteins and, especially, microRNAs that exert paracrine and endocrine effects. In this study, we investigated whether skeletal muscle‐derived exosomes (SkM‐Exo) regulate the endothelial cell functions of angiogenesis. We demonstrated that C2C12 myotube‐derived exosomes improved endothelial cell functions, assessed by the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), which were increased by 20, 23 and 40%, respectively, after SkM‐Exo exposure. The SkM‐Exo failed to activate HUVEC vascular endothelial growth factor (VEGF) signalling. The SkM‐Exo increased HUVEC reactive oxygen species and activated the nuclear factor‐κB pathway, suggesting that SkM‐Exo‐induced angiogenesis was mediated by a VEGF‐independent pathway. In addition, several angiogenic microRNAs were packaged in SkM‐Exo, with miR‐130a being particularly enriched and successfully transferred from SkM‐Exo to HUVECs. Delivery of miRNAs into endothelial cells might explain the enhancement of reactive oxygen species production and angiogenesis by SkM‐Exo. The potential angiogenic effect of SkM‐Exo could provide an effective therapy for promoting skeletal muscle angiogenesis in diseases characterized by capillary rarefaction or inadequate angiogenesis.

show abstract

“…) and muscle is known to secrete myokines (Whitham & Febbraio, ) and exosomes (Whitham et al . ) that can affect other tissues. It is currently unknown whether muscle Rac1 affects muscle cross‐talk with other organs or by which secondary factors Rac1 muscle KO improves insulin‐stimulated glucose uptake in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Rac1 muscle knockout exacerbates the detrimental effect of high‐fat diet on insulin‐stimulated muscle glucose uptake independently of Akt

Raun

Ali

Kjøbsted

et al. 2018

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Insulin resistance and perturbations in glucose metabolism underpin common lifestyle diseases such as type 2 diabetes and obesity. Insulin resistance in muscle is characterized by compromised activity of the GTPase, Ras-related C3 Botulinum toxin substrate 1 (Rac1), yet the role of Rac1 in insulin-stimulated glucose uptake in vivo and diet-induced insulin resistance is unknown. Inducible muscle-specific Rac1 knockout (Rac1 mKO) and wild type (WT) littermate mice were either fed a chow or a 60% high-fat diet (HFD). Insulin-stimulated 2-deoxy-glucose uptake, intracellular signalling, protein expression, substrate utilization, and glucose and insulin tolerance were assessed. In chow-fed mice, in vivo insulin-stimulated glucose uptake was reduced in triceps, soleus and gastrocnemius muscles from Rac1 mKO mice. HFD-induced whole body insulin resistance was exacerbated by the lack of muscle Rac1 and glucose uptake was reduced in all muscles, except for soleus. Muscle Akt (also known as protein kinase B) signalling was unaffected by diet or genotype. In adipose tissue, Rac1 mKO mice were protected from HFD-induced insulin resistance (with respect to both glucose uptake and phosphorylated-Akt), rendering their whole body glucose tolerance comparable to WT mice on HFD. Our findings show that lack of Rac1 exacerbates HFD-induced insulin resistance in skeletal muscle. Whole body glucose tolerance, however, was largely unaffected in Rac1 mKO mice, likely due to improved insulin-stimulated glucose uptake in adipose tissue. We conclude that lack of Rac1 in the context of obesity is detrimental to insulin-stimulated muscle glucose uptake in muscle independently of Akt signalling.

show abstract

Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise

Cited by 434 publications

References 68 publications

Multivesicular body and exosome pathway responses to acute exercise

Multivesicular body and exosome pathway responses to acute exercise

Skeletal muscle‐derived exosomes regulate endothelial cell functions via reactive oxygen species‐activated nuclear factor‐κB signalling

Rac1 muscle knockout exacerbates the detrimental effect of high‐fat diet on insulin‐stimulated muscle glucose uptake independently of Akt

Contact Info

Product

Resources

About