Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes

Aims/hypothesis A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes. Methods Ph...

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Published in:Diabetologia 2018-06, Vol.61 (6), p.1411-1423
Main Authors: Monaco, Cynthia M. F., Hughes, Meghan C., Ramos, Sofhia V., Varah, Nina E., Lamberz, Christian, Rahman, Fasih A., McGlory, Chris, Tarnopolsky, Mark A., Krause, Matthew P., Laham, Robert, Hawke, Thomas J., Perry, Christopher G. R.
Format: Article
Language:English
Subjects:
Adult
AMP
AMP-activated protein kinase
Autophagy
Bioenergetics
Body Mass Index
Calcium (mitochondrial)
Calcium - chemistry
Diabetes
Diabetes mellitus
Diabetes mellitus (insulin dependent)
Diabetes Mellitus, Type 1 - metabolism
Diabetes Mellitus, Type 1 - pathology
Electron microscopy
Electron transport chain
Energy Metabolism
Exercise - physiology
Female
Fluorescence spectroscopy
Human Physiology
Humans
Hydrogen peroxide
Hydrogen Peroxide - metabolism
Immunofluorescence
Insulin - metabolism
Internal Medicine
Kinases
Male
Medicine
Medicine & Public Health
Metabolic Diseases
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Microvasculature
Mitochondria
Mitochondria - metabolism
Mitochondria - ultrastructure
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscle, Skeletal - ultrastructure
Musculoskeletal system
Oxygen Consumption
Phagocytosis
Phenotypes
Physical activity
Platelet aggregation
Skeletal muscle
Tomography
Ultrastructure
Young Adult
Young adults
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Summary:Aims/hypothesis A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes. Methods Physically active, young adults (men and women) with type 1 diabetes (HbA 1c 63.0 ± 16.0 mmol/mol [7.9% ± 1.5%]) and without type 1 diabetes (control), matched for sex, age, BMI and level of physical activity, were recruited ( n  = 12/group) to undergo vastus lateralis muscle microbiopsies. Mitochondrial respiration (high-resolution respirometry), site-specific mitochondrial H 2 O 2 emission and Ca 2+ retention capacity (CRC) (spectrofluorometry) were assessed using permeabilised myofibre bundles. Electron microscopy and tomography were used to quantify mitochondrial content and investigate muscle ultrastructure. Skeletal muscle microvasculature was assessed by immunofluorescence. Results Mitochondrial oxidative capacity was significantly lower in participants with type 1 diabetes vs the control group, specifically at Complex II of the electron transport chain, without differences in mitochondrial content between groups. Muscles of those with type 1 diabetes also exhibited increased mitochondrial H 2 O 2 emission at Complex III and decreased CRC relative to control individuals. Electron tomography revealed an increase in the size and number of autophagic remnants in the muscles of participants with type 1 diabetes. Despite this, levels of the autophagic regulatory protein, phosphorylated AMP-activated protein kinase (p-AMPKα Thr172 ), and its downstream targets, phosphorylated Unc-51 like autophagy activating kinase 1 (p-ULK1 Ser555 ) and p62, was similar between groups. In addition, no differences in muscle capillary density or platelet aggregation were observed between the groups. Conclusions/interpretation Alterations in mitochondrial ultrastructure and bioenergetics are evident within the skeletal muscle of active young adults with type 1 diabetes. It is yet to be elucidated whether more rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-018-4602-6