bims-exemet 2021-08-22 papers

Issue of 2021–08–22
six papers selected by
Javier Botella Ruiz, Victoria University

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

Am J Physiol Endocrinol Metab. 2021 08 16.

Post-exercise changes in myocellular lipid droplet characteristics of young lean individuals are affected by circulatory non-esterified fatty acids.

Sabine Daemen, Nynke van Polanen, Lena Bilet, Esther Phielix, Esther Moonen-Kornips, Vera B Schrauwen-Hinderling, Patrick Schrauwen, Matthijs K C Hesselink.

Intramyocellular lipid (IMCL) content is an energy source during acute exercise. Non-esterified fatty acid (NEFA) levels can compete with IMCL utilization during exercise. IMCL content is stored as lipid droplets (LDs) that vary in size, number, subcellular distribution and in coating with LD protein PLIN5. Little is known about how these factors are affected during exercise and recovery. Here, we aimed to investigate the effects of acute exercise with and without elevated NEFA levels on intramyocellular LD size and number, intracellular distribution and PLIN5 coating, using high-resolution confocal microscopy. In a cross-over study, 9 healthy lean young men performed a 2h moderate intensity cycling protocol in the fasted (high NEFA levels) and glucose-fed state (low NEFA levels). IMCL and LD parameters were measured at baseline, directly after exercise and 4h post-exercise. We found that total IMCL content was not changed directly after exercise (irrespectively of condition), but IMCL increased 4h post-exercise in the fasting condition, which was due to an increased number of LDs rather than changes in size. The effects were predominantly detected in type I muscle fibers and in LDs coated with PLIN5. Interestingly, subsarcolemmal, but not intermyofibrillar IMCL content, was decreased directly after exercise in the fasting condition and was replenished during the 4h recovery period. In conclusion, acute exercise affects IMCL storage during exercise and recovery, particularly in type I muscle fibers, in the subsarcolemmal region and in the presence of PLIN5. Moreover, the effects of exercise on IMCL content are affected by plasma NEFA levels.

Keywords: Exercise; Lipid droplets; Muscle

DOI: https://doi.org/10.1152/ajpendo.00654.2020

Diabetologia. 2021 Aug 17.

Twenty-four hour assessments of substrate oxidation reveal differences in metabolic flexibility in type 2 diabetes that are improved with aerobic training.

Elvis A Carnero, Christopher P Bock, Giovanna Distefano, Karen D Corbin, Natalie A Stephens, Richard E Pratley, Steven R Smith, Bret H Goodpaster, Lauren M Sparks.

AIMS/HYPOTHESIS: The aim of this study was to assess metabolic flexibility (MetFlex) in participants with type 2 diabetes within the physiologically relevant conditions of sleeping, the post-absorptive (fasting) state and during meals using 24 h whole-room indirect calorimetry (WRIC) and to determine the impact of aerobic training on these novel features of MetFlex.
METHODS: Normal-weight, active healthy individuals (active; n = 9), obese individuals without type 2 diabetes (ND; n = 9) and obese individuals with type 2 diabetes (n = 23) completed baseline metabolic assessments. The type 2 diabetes group underwent a 10 week supervised aerobic training intervention and repeated the metabolic assessments. MetFlex was assessed by indirect calorimetry in response to insulin infusion and during a 24 h period in a whole-room indirect calorimeter. Indices of MetFlex evaluated by WRIC included mean RQ and RQ kinetic responses after ingesting a standard high-carbohydrate breakfast (RQBF) and sleep RQ (RQsleep). Muscle mitochondrial energetics were assessed in the vastus lateralis muscle in vivo and ex vivo using 31P-magnetic resonance spectroscopy and high-resolution respirometry, respectively.
RESULTS: The three groups had significantly different RQsleep values (active 0.823 ± 0.04, ND 0.860 ± 0.01, type 2 diabetes 0.842 ± 0.03; p < 0.05). The active group had significantly faster RQBF and more stable RQsleep responses than the ND and type 2 diabetes groups, as demonstrated by steeper and flatter slopes, respectively. Following the training intervention, the type 2 diabetes group displayed significantly increased RQBF slope. Several indices of RQ kinetics had significant associations with in vivo and ex vivo muscle mitochondrial capacities.
CONCLUSIONS/INTERPRETATION: Twenty-four hour WRIC revealed that physiological RQ responses exemplify differences in MetFlex across a spectrum of metabolic health and correlated with skeletal muscle mitochondrial energetics. Defects in certain features of MetFlex were improved with aerobic training, emphasising the need to assess multiple aspects of MetFlex and disentangle insulin resistance from MetFlex in type 2 diabetes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01911104.
FUNDING: This study was funded by the ADA (grant no. 7-13-JF-53).

Keywords: Clamp; Exercise intervention; Meal challenge; Metabolic flexibility; Mitochondrial capacity; Whole-room indirect calorimetry

DOI: https://doi.org/10.1007/s00125-021-05535-y

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

Clin Interv Aging. 2021 ;16 1485-1501

Effect of 5 Years of Exercise Intervention at Different Intensities on Brain Structure in Older Adults from the General Population: A Generation 100 Substudy.

Jasmine Pani, Line S Reitlo, Hallvard Røe Evensmoen, Stian Lydersen, Ulrik Wisløff, Dorthe Stensvold, Asta K Håberg.

Purpose: The aim was to examine the effect of a 5-year exercise intervention at different intensities on brain structure in older adults from the general population partaking in the randomized controlled trial Generation 100 Study.
Participants and Methods: Generation 100 Study participants were invited to a longitudinal neuroimaging study before randomization. A total of 105 participants (52 women, 70-77 years) volunteered. Participants were randomized into supervised exercise twice a week performing high intensity interval training in 4×4 intervals at ~90% peak heart rate (HIIT, n = 33) or 50 minutes of moderate intensity continuous training at ~70% of peak heart rate (MICT, n = 24). The control group (n = 48) followed the national physical activity guidelines of ≥30 min physical activity daily. Brain MRI at 3T, clinical and cardiorespiratory fitness (CRF), measured as peak oxygen uptake, were collected at baseline, and after 1, 3, and 5 years of intervention. Brain volumes and cortical thickness were derived from T1 weighted 3D MRI data using FreeSurfer. The effect of HIIT or MICT on brain volumes over time was investigated with linear mixed models, while linear regressions examined the effect of baseline CRF on brain volumes at later time points.
Results: Adherence in each group was between 79 and 94% after 5 years. CRF increased significantly in all groups during the first year. Compared to controls, the HIIT group had significantly increased hippocampal atrophy located to CA1 and hippocampal body, though within normal range, and the MICT group greater thalamic atrophy. No other effects of intervention group were found. CRF across the intervention was not associated with brain structure, but CRF at baseline was positively associated with cortical volume at all later time points.
Conclusion: Higher baseline CRF reduced 5-year cortical atrophy rate in older adults, while following physical activity guidelines was associated with the lowest hippocampal and thalamic atrophy rates.

Keywords: CNS; aging; brain reserve; limbic; morphometry

DOI: https://doi.org/10.2147/CIA.S318679

Nat Metab. 2021 Aug;3(8): 1058-1070

Exercise hormone irisin is a critical regulator of cognitive function.

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

DOI: https://doi.org/10.1038/s42255-021-00438-z