1. Normal to enhanced intrinsic mitochondrial respiration in skeletal muscle of middle- to older-aged women and men with uncomplicated type 1 diabetes.
- Author
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Monaco CMF, Tarnopolsky MA, Dial AG, Nederveen JP, Rebalka IA, Nguyen M, Turner LV, Perry CGR, Ljubicic V, and Hawke TJ
- Subjects
- Adult, Aged, Electron Transport Complex I metabolism, Electron Transport Complex II metabolism, Female, Humans, Male, Middle Aged, Oxidative Phosphorylation, Oxygen Consumption physiology, Respiratory Mechanics, Cell Respiration physiology, Diabetes Mellitus, Type 1 metabolism, Mitochondria, Muscle metabolism, Muscle, Skeletal metabolism
- Abstract
Aims/hypothesis: This study interrogated mitochondrial respiratory function and content in skeletal muscle biopsies of healthy adults between 30 and 72 years old with and without uncomplicated type 1 diabetes., Methods: Participants (12 women/nine men) with type 1 diabetes (48 ± 11 years of age), without overt complications, were matched for age, sex, BMI and level of physical activity to participants without diabetes (control participants) (49 ± 12 years of age). Participants underwent a Bergström biopsy of the vastus lateralis to assess mitochondrial respiratory function using high-resolution respirometry and citrate synthase activity. Electron microscopy was used to quantify mitochondrial content and cristae (pixel) density., Results: Mean mitochondrial area density was 27% lower (p = 0.006) in participants with type 1 diabetes compared with control participants. This was largely due to smaller mitochondrial fragments in women with type 1 diabetes (-18%, p = 0.057), as opposed to a decrease in the total number of mitochondrial fragments in men with diabetes (-28%, p = 0.130). Mitochondrial respiratory measures, whether estimated per milligram of tissue (i.e. mass-specific) or normalised to area density (i.e. intrinsic mitochondrial function), differed between cohorts, and demonstrated sexual dimorphism. Mass-specific mitochondrial oxidative phosphorylation (OXPHOS) capacity with the substrates for complex I and complex II (C
I + II ) was significantly lower (-24%, p = 0.033) in women with type 1 diabetes compared with control participants, whereas mass-specific OXPHOS capacities with substrates for complex I only (pyruvate [CI pyr ] or glutamate [CI glu ]) or complex II only (succinate [CII succ ]) were not different (p > 0.404). No statistical differences (p > 0.397) were found in mass-specific OXPHOS capacity in men with type 1 diabetes compared with control participants despite a 42% non-significant increase in CI glu OXPHOS capacity (p = 0.218). In contrast, intrinsic CI + II OXPHOS capacity was not different in women with type 1 diabetes (+5%, p = 0.378), whereas in men with type 1 diabetes it was 25% higher (p = 0.163) compared with control participants. Men with type 1 diabetes also demonstrated higher intrinsic OXPHOS capacity for CI pyr (+50%, p = 0.159), CI glu (+88%, p = 0.033) and CII succ (+28%, p = 0.123), as well as higher intrinsic respiratory rates with low (more physiological) concentrations of either ADP, pyruvate, glutamate or succinate (p < 0.012). Women with type 1 diabetes had higher (p < 0.003) intrinsic respiratory rates with low concentrations of succinate only. Calculated aerobic fitness (Physical Working Capacity Test [PWC130 ]) showed a strong relationship with mitochondrial respiratory function and content in the type 1 diabetes cohort., Conclusions/interpretation: In middle- to older-aged adults with uncomplicated type 1 diabetes, we conclude that skeletal muscle mitochondria differentially adapt to type 1 diabetes and demonstrate sexual dimorphism. Importantly, these cellular alterations were significantly associated with our metric of aerobic fitness (PWC130 ) and preceded notable impairments in skeletal mass and strength., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2021
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