bims-misrem 2021-08-22 papers

Diabetologia. 2021 Aug 14.

Normal to enhanced intrinsic mitochondrial respiration in skeletal muscle of middle- to older-aged women and men with uncomplicated type 1 diabetes.

Cynthia M F Monaco, Mark A Tarnopolsky, Athan G Dial, Joshua P Nederveen, Irena A Rebalka, Maria Nguyen, Lauren V Turner, Christopher G R Perry, Vladimir Ljubicic, Thomas J Hawke.

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 (CI + 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.

Keywords: Aerobic fitness; Mitochondria; Older adults; Oxidative phosphorylation; Skeletal muscle; Type 1 diabetes

DOI: https://doi.org/10.1007/s00125-021-05540-1

Cell Calcium. 2021 Aug 05. pii: S0143-4160(21)00107-X. [Epub ahead of print]98 102453

Ca2+ handling at the mitochondria-ER contact sites in neurodegeneration.

Dmitry Lim, Giulia Dematteis, Laura Tapella, Armando A Genazzani, Tito Calì, Marisa Brini, Alexei Verkhratsky.

Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are morpho-functional units, formed at the loci of close apposition of the ER-forming endomembrane and outer mitochondrial membrane (OMM). These sites contribute to fundamental cellular processes including lipid biosynthesis, autophagy, apoptosis, ER-stress and calcium (Ca2+) signalling. At MERCS, Ca2+ ions are transferred from the ER directly to mitochondria through a core protein complex composed of inositol-1,4,5 trisphosphate receptor (InsP3R), voltage-gated anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU) and adaptor protein glucose-regulated protein 75 (Grp75); this complex is regulated by several associated proteins. Deregulation of ER-mitochondria Ca2+ transfer contributes to pathogenesis of neurodegenerative and other diseases. The efficacy of Ca2+ transfer between ER and mitochondria depends on the protein composition of MERCS, which controls ER-mitochondria interaction regulating, for example, the transversal distance between ER membrane and OMM and the extension of the longitudinal interface between ER and mitochondria. These parameters are altered in neurodegeneration. Here we overview the ER and mitochondrial Ca2+ homeostasis, the composition of ER-mitochondrial Ca2+ transfer machinery and alterations of the ER-mitochondria Ca2+ transfer in three major neurodegenerative diseases: motor neurone diseases, Parkinson disease and Alzheimer's disease.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Endoplasmic reticulum; Mitochondria; Mitochondria-ER contact sites; Motor neurone disease; Parkinson's disease

DOI: https://doi.org/10.1016/j.ceca.2021.102453

Appl Physiol Nutr Metab. 2021 Aug 16.

Effect of Local Heat Application During Exercise on Gene Expression Related to Mitochondrial Homeostasis.

Nattie O'Reilly, Christopher Collins, Mark L McGlynn, Dustin Russel Slivka.

Determine the impact of local muscle heating during endurance exercise on human skeletal muscle mitochondrial-related gene expression. Twelve subjects (25±6 yrs, 177±8 cm, 78±16 kg, and VO2peak peak 45±8 ml·kg-1·min-1) cycled with one leg heated (HOT) and the other serving as a control (CON). Skin and intramuscular temperatures were taken before temperature intervention (Pre), after 30 min (Pre30), after exercise (Post) and four hours after exercise (4Post). Muscle biopsies were taken from each leg at Pre and 4Post. Intramuscular temperature increased within HOT (34.4±0.7ºC to 36.1±0.5ºC, p<0.001) and was higher than CON at Pre30 (34.0±0.7ºC, p<0.001). However, temperatures at POST were similar (HOT 38.4±0.7ºC, CON 38.3±0.5ºC, p=0.661). Skin temperature was higher than CON at Post30 (30.3±1.0ºC, p<0.001) and Post (HOT 34.6±0.9ºC, CON 32.3±1.6ºC, p<0.001). PGC-1α, VEGF and NRF2 mRNA increased with exercise (p<0.05) but was not altered with heating (p>0.05). TFAM increased after exercise with heat application (HOT, p=0.019) but not with exercise alone (CON, p=0.422). There was no difference in NRF1, ESRRα, or any of the mitophagy related genes in response to exercise or temperature (p>0.05). In conclusion, TFAM is enhanced by local heat application during endurance exercise, whereas other genes related to mitochondrial homeostasis are unaffected. Novelty: The main finding of this study is that localized heating increased TFAM mRNA expression. The normal exercise-induced increased PGC-1α gene expression was unaltered by local muscle heating.

DOI: https://doi.org/10.1139/apnm-2021-0346