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

作者：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

来源：Diabetologia, 2018, 61(6): 1411-1423.

DOI：10.1007/s00125-018-4602-6

• Calciumtolerance
• Capillary density
• Mitochondria
• Myopathy
• Reactive oxygen species
• Skeletalmuscle
• 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 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 H2O2 emission and Ca2+ 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 H2O2 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-AMPK alpha(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.

• 出版日期2018-6