Skeletal muscle mitochondrial health in type 1 diabetes: the role of exercise capacity and lifestyle factors

Figures

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  Fig. 1. Skeletal muscle mitochondrial density, number and size in individuals with and without type 1 diabetes. (a, b) Representative images of the intermyofibrillar region in a control participant (a) and a participant with type 1 diabetes (b). (c) Intermyofibrillar mitochondrial density. (d) Mean individual intermyofibrillar mitochondrial area. (e) Number of intermyofibrillar mitochondria per µm2. (f, g) Representative images of the subsarcolemmal region in a control participant (f) and a participant with type 1 diabetes (g). (h) Subsarcolemmal mitochondrial density. (i) Mean individual subsarcolemmal mitochondrial area. (j) Number of subsarcolemmal mitochondria per µm2. n=16 for the type 1 diabetes group, n=15 for the control group. Columns and error bars represent means ± SD, circles reflect individual data points. Scale bar, 500 nm. T1DM, type 1 diabetes mellitus

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  Fig. 2. Skeletal muscle mitochondrial respiration in individuals with and without type 1 diabetes. (a) Leak respiration in the presence of NADH-linked substrates and no ADP. (b) Maximal OXPHOS capacity in the presence of saturating (ADP) and convergent electron flow through complexes I and II. (c) Electron transfer capacity measured in the presence of optimal concentrations of uncoupler. (d) Intrinsic leak respiration. (e) Intrinsic maximal OXPHOS capacity. (f) Intrinsic electron transfer capacity. n=15 (a–c) or n=14 (d–f) for each comparison in both groups. Columns and error bars represent means ± SD, circles reflect individual data points. *p<0.05. JO2, mitochondrial oxygen consumption; T1DM, type 1 diabetes mellitus

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  Fig. 3. Skeletal muscle nutrient accumulation in individuals with and without type 1 diabetes. (a, b) Representative images showing skeletal muscle glycogen (a) and intramyocellular lipid deposition (b) in a control participant and a participant with type 1 diabetes. (c, d) Muscle glycogen score (c) and intramyocellular lipid deposition score (d) in the type 1 diabetes and control groups. n=16 (type 1 diabetes group) or n=15 (control group). Nine hundred and twenty-six images were scored in a systematic, blinded fashion by three experienced raters, with the score for each participant reflecting the mean across all images from that participant. Lipid score was correlated with mitochondrial fragmentation in control participants (r=0.68, p=0.0057) but not in participants with type 1 diabetes (r=−0.34, p=0.20). Columns and error bars represent means ± SD, circles reflect individual data points. Scale bar, 500 nm. T1DM, type 1 diabetes mellitus

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  Fig. 4. Skeletal muscle capillarisation in control individuals (n=17) and individuals with type 1 diabetes (n=15). (a) Representative images used for quantification of skeletal muscle capillarisation in a healthy control participant and a participant with type 1 diabetes. Images were acquired at ×20 magnification. (b, c) Capillary density (b) and capillary-to-fibre ratio (c) in the type 1 diabetes and control groups. (d) Representative electron micrograph used for quantification of skeletal muscle capillary basement membrane thickness. (e) Skeletal muscle capillary basement membrane thickness in control participants (n=7) and participants with type 1 diabetes (n=5). Columns and error bars represent means ± SD, circles reflect individual data points. Scale bar, 500 nm. ns, no significant difference; T1DM, type 1 diabetes mellitus

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  Fig. 5. Mitochondrial characteristics in healthy control individuals and individuals with type 1 diabetes, with the type 1 diabetes group split by maximal oxygen uptake (a–d), HbA1c concentrations (e–h) and BMI (i–l). (a, e) Leak respiration in the presence of NADH-linked substrates and no ADP. (b, f) NADH-linked respiration in the presence of NADH-linked substrates and saturating ADP. (c, g) Maximal OXPHOS capacity in the presence of saturating ADP and convergent electron flow through complexes I and II. (d, h) Electron transfer capacity measured in the presence of optimal concentrations of uncoupler. (i) Intermyofibrillar mitochondrial density. (j) Subsarcolemmal mitochondrial density. (k) Intermyofibrillar mitochondrial fragmentation index. (l) Subsarcolemmal mitochondrial fragmentation index. (a–d) n=15 control participants, n=8 participants with type 1 diabetes and low \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{V}{\text{O}}_{\text{2max}}$$\end{document}V˙O2max, n=6 participants with type 1…

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  Fig. 6. Correlates of mitochondrial respiration, density and fragmentation in individuals with type 1 diabetes. (a–d) Correlations between maximal oxygen uptake (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{V}{\text{O}}_{\text{2max}}$$\end{document}V˙O2max) and intermyofibrillar mitochondrial density (a), subsarcolemmal mitochondrial density (b), intermyofibrillar mitochondrial fragmentation index (c) and subsarcolemmal mitochondrial fragmentation index (d). (e–h) Correlations between HbA1c and leak respiration (e), NADH-linked respiration (f), OXPHOS capacity (g) and electron transfer capacity (h). (i–l) Correlations between BMI and intermyofibrillar mitochondrial density (i), intermyofibrillar mitochondrial fragmentation index (j), subsarcolemmal mitochondrial density (k) and subsarcolemmal mitochondrial fragmentation index (l). n=16 (a–d, i–l) or n=14 participants (e–h). Circles reflect individual participant data whereas dashed lines indicate line of best fit for significant correlations. *p<0.05,…