bims-exemet 2021-03-14 papers

bims-exemet

Biomed News

on Exercise metabolism

Issue of 2021–03–14
eleven papers selected by
Javier Botella Ruiz, Victoria University

The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle.
Reducing NF-κB signalling nutritionally is associated with expedited recovery of skeletal muscle function after damage.
Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle.
Effects of Ultramarathon Running on Mitochondrial Function of Platelets and Oxidative Stress Parameters: A Pilot Study.
Hyperinsulinemia Induced Altered Insulin Signaling Pathway in Muscle of High Fat- and Carbohydrate-Fed Rats: Effect of Exercise.
AMPK is indispensable for overload-induced muscle glucose uptake and glycogenesis but dispensable for inducing hypertrophy in mice.
Muscular HSP70 content is higher in elderly compared to young, but is normalized after 12 weeks of strength training.
Pyrroloquinoline quinone protects against exercise-induced fatigue and oxidative damage via improving mitochondrial function in mice.
Mitochondrial bioenergetic pathways in blood leukocyte transcriptome decrease after intensive weight loss but are rescued following weight regain in female physique athletes.
Skeletal Muscle Adaptations Following 80 Weeks of Resistance Exercise in Older Adults.
Fragile bones of elite cyclists: to treat or not to treat?

Front Physiol. 2021 ;12 619447

The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle.

Mohd-Firdaus Maasar, Daniel C Turner, Piotr P Gorski, Robert A Seaborne, Juliette A Strauss, Sam O Shepherd, Matt Cocks, Nicolas J Pillon, Juleen R Zierath, Andrew T Hulton, Barry Drust, Adam P Sharples.

  The methylome and transcriptome signatures following exercise that are physiologically and metabolically relevant to sporting contexts such as team sports or health prescription scenarios (e.g., high intensity interval training/HIIT) has not been investigated. To explore this, we performed two different sport/exercise relevant high-intensity running protocols in five male sport team members using a repeated measures design of: (1) change of direction (COD) versus; (2) straight line (ST) running exercise with a wash-out period of at least 2 weeks between trials. Skeletal muscle biopsies collected from the vastus lateralis 30 min and 24 h post exercise, were assayed using 850K methylation arrays and a comparative analysis with recent (subject-unmatched) sprint and acute aerobic exercise meta-analysis transcriptomes was performed. Despite COD and ST exercise being matched for classically defined intensity measures (speed × distance and number of accelerations/decelerations), COD exercise elicited greater movement (GPS-Playerload), physiological (HR), metabolic (lactate) as well as central and peripheral (differential RPE) exertion measures compared with ST exercise, suggesting COD exercise evoked a higher exercise intensity. The exercise response alone across both conditions evoked extensive alterations in the methylome 30 min and 24 h post exercise, particularly in MAPK, AMPK and axon guidance pathways. COD evoked a considerably greater hypomethylated signature across the genome compared with ST exercise, particularly at 30 min post exercise, enriched in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. Comparative methylome analysis with sprint running transcriptomes identified considerable overlap, with 49% of genes that were altered at the expression level also differentially methylated after COD exercise. After differential methylated region analysis, we observed that VEGFA and its downstream nuclear transcription factor, NR4A1 had enriched hypomethylation within their promoter regions. VEGFA and NR4A1 were also significantly upregulated in the sprint transcriptome and meta-analysis of exercise transcriptomes. We also confirmed increased gene expression of VEGFA, and considerably larger increases in the expression of canonical metabolic genes PPARGC1A (that encodes PGC1-α) and NR4A3 in COD vs. ST exercise. Overall, we demonstrate that increased physiological/metabolic load via COD exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise.

Keywords:  AMPK; DNA methylation; MAPK; NR4A1 (Nur77); NR4A3; PGC1 alpha; VEGF; change of direction

DOI:  https://doi.org/10.3389/fphys.2021.619447
J Clin Endocrinol Metab. 2021 Feb 26. pii: dgab106. [Epub ahead of print]

Reducing NF-κB signalling nutritionally is associated with expedited recovery of skeletal muscle function after damage.

Tom S O Jameson, George F Pavis, Marlou L Dirks, Benjamin P Lee, Doaa R Abdelrahman, Andrew J Murton, Craig Porter, Nima Alamdari, Catherine R Mikus, Benjamin T Wall, Francis B Stephens.

   CONTEXT: The early events regulating the remodelling programme following skeletal muscle damage are poorly understood.
OBJECTIVE: The objective of this study was to determine the association between myofibrillar protein synthesis (myoPS) and nuclear factor-kappa B (NF-κB) signalling by nutritionally accelerating recovery of muscle function following damage.
DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Healthy males and females consumed daily post-exercise and pre-bed protein-polyphenol (PP; n=9; 4 females) or isocaloric maltodextrin placebo (PLA; n=9; 3 females) drinks (parallel design), 6 days before and 3 days after 300 unilateral eccentric quadriceps contractions (EC) during complete dietary control.
MAIN OUTCOME MEASURES: Muscle function was assessed daily, and skeletal muscle biopsies were taken after 24, 27 and 36 h for measurements of myoPS rates using deuterated water, and gene ontology and NF-κB signalling analysis using an RT-qPCR gene array.
RESULTS: EC impaired muscle function for 48 h in PLA, but for just 24 h in PP (P=0.047). EC increased myoPS compared to the control leg during post-exercise (24-27 h; 0.14±0.01 vs 0.11±0.01%·h -1, respectively; P=0.075) and overnight periods (27-36 h; 0.10±0.01 vs 0.07±0.01%·h -1, respectively; P=0.020), but was not further increased by PP (P>0.05). PP decreased post-exercise and overnight muscle IL1R1 (PLA=2.8±0.4, PP=1.1±0.4 and PLA=1.9±0.4, PP=0.3±0.4 log2 fold change, respectively) and IL1RL1 (PLA=4.9±0.7, PP=1.6±0.8 and PLA=3.7±0.6, PP=0.7±0.7 log2 fold change, respectively) mRNA expression (P<0.05) and downstream NF-κB signalling compared to PLA.
CONCLUSION: PP ingestion likely accelerates recovery of muscle function by attenuating inflammatory NF-κB transcriptional signalling, possibly to reduce aberrant tissue degradation rather than increase myoPS rates.

Keywords:  Inflammation; deuterated water; muscle damage; protein-polyphenol

DOI:  https://doi.org/10.1210/clinem/dgab106
Am J Physiol Endocrinol Metab. 2021 Mar 08.

Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle.

Yingzi He, Ruojun Qiu, Beibei Wu, Weiwei Gui, Xihua Lin, Hong Li, Fenping Zheng.

  Exercise improves obesity-induced insulin resistance and metabolic disorders via mechanisms that remain unclear. Here, we show that the levels of the hepatokine transthyretin (TTR) in circulation are elevated in insulin-resistant individuals including high-fat diet (HFD)-induced obese mice, db/db mice, and patients with metabolic syndrome. Liver Ttr mRNA and circulating TTR levels were reduced in mice by treadmill training, as was the TTR levels in quadriceps femoris muscle; however, AMPK signalling activity was enhanced. Transgenic overexpression of TTR or injection of purified TTR triggered insulin resistance in mice fed on regular chow (RC). Furthermore, TTR overexpression reduced the beneficial effects of exercise on insulin sensitivity in HFD-fed mice. TTR was internalized by muscle cells via the membrane receptor Grp78 and the internalization into the quadriceps femoris was reduced by treadmill training. The TTR/Grp78 combination in C2C12 cells was increased, whereas the AMPK activity of C2C12 cells was decreased as the TTR concentration rose. Additionally, Grp78 silencing prevented the TTR internalization and reversed its inhibitory effect on AMPK activity in C2C12 cells. Our study suggests that elevated circulating TTR may contribute to insulin resistance and counteract the exercise-induced insulin sensitivity improvement; the TTR suppression might be an adaptive response to exercise through enhancing AMPK activity in skeletal muscles.

Keywords:  AMPK; Grp78; Transthyretin; exercise; insulin resistance

DOI:  https://doi.org/10.1152/ajpendo.00495.2020
Front Physiol. 2021 ;12 632664

Effects of Ultramarathon Running on Mitochondrial Function of Platelets and Oxidative Stress Parameters: A Pilot Study.

Florian Hoppel, Elisa Calabria, Dominik H Pesta, Wilhelm Kantner-Rumplmair, Erich Gnaiger, Martin Burtscher.

  Only a few studies have evaluated changes in mitochondrial function and oxidative stress associated with ultramarathon running. Invasive biopsies are needed to assess mitochondrial function of skeletal muscle, which may not be well tolerated by some individuals. Platelets (PLTs) as a metabolically highly active and homogenous cell population were suggested as a potentially valuable surrogate to investigate mitochondrial function. Thus, this study was aimed to evaluate mitochondrial function of PLTs and its association with individual race performance and markers of oxidative stress, muscle damage and renal dysfunction. Race performance and mitochondrial function (high-resolution respirometry, HRR) of PLTs using different substrates inducing ROUTINE, LEAK, N-pathway control state (Complex I linked oxidative phosphorylation; CI, OXPHOS), NS-pathway control state (CI + II linked OXPHOS and electron transfer pathway; ET), S-pathway control state (CII linked ET) as well as parameters of oxidative stress and antioxidant capacity, and markers of muscle and renal injury were assessed in eight male ultramarathon runners (26-45 years) before, immediately after and 24 h after an ultramarathon race (PRE, POST, and REC). Ultramarathon running induced an increase in LEAK O2 flux of PLT mitochondria and slight, largely non-significant changes in the oxidant/antioxidant balance. Levels of creatine kinase (CK), lactate dehydrogenase (LDH), blood urea nitrogen, and creatinine were all significantly elevated POST and remained high in REC. There were inverse correlations between race time and N-linked substrate state PRE-POST, and changes in CK and LDH levels were significantly related to PLT mitochondrial LEAK and N-linked respiration PRE. Although race-related changes in respirometry parameters of PLT mitochondria were rather small, a somewhat more pronounced increase in the relative N-linked respiration in faster runners might suggest PLT CI as indicator of physical fitness. The higher PLT LEAK PRE and diminished increase of CK during the race may represent a prophylactic preconditioning and the slight but non-significant elevation of the antioxidant potential post-race as a protective consequence of the race-related oxidative stress and potential threat to the kidney. Our findings point toward an interrelationship between mitochondrial function of PLTs, individual fitness levels and extreme physical and metal stresses, which stimulates further research.

Keywords:  acute kidney injury; mitochondrial function; muscle damage; platelets; ultramarathon running

DOI:  https://doi.org/10.3389/fphys.2021.632664
J Diabetes Res. 2021 ;2021 5123241

Hyperinsulinemia Induced Altered Insulin Signaling Pathway in Muscle of High Fat- and Carbohydrate-Fed Rats: Effect of Exercise.

Anu Joseph, S Parvathy, Koyikkal Karthikeya Varma.

Insulin resistance is a state of impaired responsiveness to insulin action. This condition not only results in deficient glucose uptake but increases the risk for cardiovascular diseases (CVD), stroke, and obesity. The present work investigates the molecular mechanisms of high carbohydrate and fat diet in inducing prediabetic hyperinsulinemia and effect of exercise on InsR signaling events, muscular AChE, and lactate dehydrogenase activity. Adult male Wistar rats were divided into the control (C) diet group, high-carbohydrate diet (HCD) group, high-fat diet (HFD) group, and HCD and HFD groups with exercise (HCD Ex and HFD Ex, respectively). Acetyl choline esterase activity, lactate dehydrogenase activity, total lactate levels, IRS1 phosphorylations, and Glut4 expression patterns were studied in the muscle tissue among these groups. High carbohydrate and fat feeding led to hyperinsulinemic status with reduced acetylcholine esterase (AChE) activity and impaired phosphorylation of IRS1 along with increased lactate concentrations in the muscle. Exercise significantly upregulated phosphoinositide 3 kinase (PI3K) docking site phosphorylation and downregulated the negative IRS1 phosphorylations thereby increasing the glucose transporter (GLUT) expressions and reducing the lactate accumulation. Also, the levels of second messengers like IP3 and cAMP were increased with exercise. Increased second messenger levels induce calcium release thereby activating the downstream pathway promoting the translocation of GLUT4 to the plasma membrane. Our results showed that the metabolic and signaling pathway dysregulations seen during diet-induced hyperinsulinemia, a metabolic condition seen during the early stages in the development of prediabetes, were improved with vigorous physical exercise. Thus, exercise can be considered as an excellent management approach over drug therapy for diabetes and its complications.

DOI: https://doi.org/10.1155/2021/5123241
FASEB J. 2021 Apr;35(4): e21459

AMPK is indispensable for overload-induced muscle glucose uptake and glycogenesis but dispensable for inducing hypertrophy in mice.

Kohei Kido, Tatsuro Egawa, Haruna Fujiyoshi, Hikari Suzuki, Kentaro Kawanaka, Tatsuya Hayashi.

  Chronic muscle loading (overload) induces skeletal muscles to undergo hypertrophy and to increase glucose uptake. Although AMP-activated protein kinase (AMPK) reportedly serves as a negative regulator of hypertrophy and a positive regulator of glucose uptake, its role in overload-induced skeletal muscle hypertrophy and glucose uptake is unclear. This study aimed to determine whether AMPK regulates overload-induced hypertrophy and glucose uptake in skeletal muscles. To this end, skeletal muscle overload was induced through unilateral synergist ablations in wild-type (WT) and transgenic mice, expressing the dominant-negative mutation of AMPK (AMPK-DN). After 14 days, parameters, including muscle fiber cross-sectional area (CSA), glycogen level, and in vivo [3 H]-2-deoxy-D-glucose uptake, were assessed. No significant difference was observed in body weight or blood glucose level between the WT and AMPK-DN mice. However, the 14-day muscle overload activated the AMPK pathway in WT mice skeletal muscle, whereas this response was impaired in the AMPK-DN mice. Despite a normal CSA gain in each fiber type, the AMPK-DN mice demonstrated a significant impairment of overload-induced muscle glucose uptake and glycogenesis, compared to WT mice. Moreover, 14-day overload-induced changes in GLUT4 and HKII expression levels were reduced in AMPK-DN mice, compared to WT mice. This study demonstrated that AMPK activation is indispensable for overload-induced muscle glucose uptake and glycogenesis; however, it is dispensable for the induction of hypertrophy in AMPK-DN mice. Furthermore, the AMPK/GLUT4 and HKII axes may regulate overload-induced muscle glucose uptake and glycogenesis.

Keywords:  AMP-activated protein kinase; functional overload; glucose uptake; hypertrophy; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202002164R
Eur J Appl Physiol. 2021 Mar 07.

Muscular HSP70 content is higher in elderly compared to young, but is normalized after 12 weeks of strength training.

K T Cumming, N H Kvamme, L Schaad, I Ugelstad, T Raastad.

   PURPOSE: Aging is associated with increased myocellular stress and loss of muscle mass and function. Heat shock proteins (HSPs) are upregulated during periods of stress as part of the cells protective system. Exercise can affect both acute HSP regulation and when repeated regularly counteract unhealthy age-related changes in the muscle. Few studies have investigated effects of exercise on HSP content in elderly. The aim of the study was to compare muscular HSP levels in young and elderly and to investigate how training affects HSP content in muscles from aged males and females.
METHODS: Thirty-eight elderly were randomized to 12 weeks of strength training (STG), functional strength training (FTG) or a control group (C). To compare elderly to young, 13 untrained young performed 11 weeks of strength training (Y). Muscle biopsies were collected before and after the intervention and analyzed for HSP27, αB-crystallin and HSP70.
RESULTS: Baseline HSP70 were 35% higher in elderly than in young, whereas there were no differences between young and elderly in HSP27 or αB-crystallin. After the training intervention, HSP70 were reduced in STG (- 33 ± 32%; P = 0.001) and FTG (- 28 ± 30%; P = 0.012). The decrease in HSP70 was more pronounced in the oldest. In contrast, Y increased HSP27 (134 ± 1%; P < 0.001) and αB-crystallin (84 ± 94%; P = 0.008).
CONCLUSION: Twelve weeks of STG or FTG decreased the initial high levels of HSP70 in aged muscles. Thus, regular strength training can normalize some of the increases in cellular stress associated with normal aging, and lead to a healthier cellular environment in aged muscle cells.

Keywords:  Aging; Functional training; Heat shock protein; Skeletal muscle; Strength training

DOI:  https://doi.org/10.1007/s00421-021-04633-4
FASEB J. 2021 Apr;35(4): e21394

Pyrroloquinoline quinone protects against exercise-induced fatigue and oxidative damage via improving mitochondrial function in mice.

Lixia Liu, Yingyong Zhang, Tao Liu, Chongrong Ke, Jianzhong Huang, Yajuan Fu, Zhang Lin, Fengjuan Chen, Xiuqin Wu, Qi Chen.

  Pyrroloquinoline quinone (PQQ) has a variety of biological functions. However, rare attention has been paid to its effects on exercise-induced damage. Here, we assessed the potential protective effects of PQQ against the fatigue and oxidative damage caused by repeated exhaustive exercise, and studied the underlying mechanism. The models for exercise-induced fatigue were established, and the parameters were measured, including the time to exhaustion (TTE), biochemical indicators, the expression of nuclear factor kappa B (NF-κB) and inflammatory cytokines and so on. Besides, the mitochondrial function was evaluated by the morphology, membrane potential, respiratory function, adenosine triphosphate (ATP) levels, and the application of the mitochondrial complex I inhibitor. The results demonstrate that PQQ prolongs TTE, causes the decrease in the activity of serum creatine kinase and lactate dehydrogenase, increases the activity of antioxidant enzymes, inhibits the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and diminishes the over expression of NF-κB (p65) and inflammatory mediators. Furthermore, PQQ preserves normal mitochondrial function. Particularly, PQQ reduces the accumulation of ROS triggered by the mitochondrial complex I inhibitor. These data suggest that PQQ can significantly protect mice from exercise-induced fatigue and oxidative damage by improving mitochondrial function. These data also suggest that PQQ controls mitochondrial activity through directly affecting the NADH dehydrogenase.

Keywords:  PQQ; damage; exercise; fatigue; mitochondria

DOI:  https://doi.org/10.1096/fj.202001977RR
FASEB J. 2021 Apr;35(4): e21484

Mitochondrial bioenergetic pathways in blood leukocyte transcriptome decrease after intensive weight loss but are rescued following weight regain in female physique athletes.

Heikki V Sarin, Eija Pirinen, Kirsi H Pietiläinen, Ville Isola, Keijo Häkkinen, Markus Perola, Juha J Hulmi.

  Prolonged periods of energy deficit leading to weight loss induce metabolic adaptations resulting in reduced energy expenditure, but the mechanisms for energy conservation are incompletely understood. We examined 42 healthy athletic females (age 27.5 ± 4.0 years, body mass index 23.4 ± 1.7 kg/m2 ) who volunteered into either a group dieting for physique competition (n = 25) or a control group (n = 17). The diet group substantially reduced their energy intake and moderately increased exercise levels to induce loss of fat mass that was regained during a voluntary weight regain period. The control group maintained their typical lifestyle habits and body mass as instructed. From the diet group, fasting blood samples were drawn at baseline (PRE), after 4- to 5-month weight loss (PRE-MID), and after 4- to 5-month weight regain (MID-POST) as well as from the control group at similar intervals. Blood was analyzed to determine leukocyte transcriptome by RNA-Sequencing and serum metabolome by nuclear magnetic resonance (NMR) platform. The intensive weight loss period induced several metabolic adaptations, including a prominent suppression of transcriptomic signature for mitochondrial OXPHOS and ribosome biogenesis. The upstream regulator analysis suggested that this reprogramming of cellular energy metabolism may be mediated via AMPK/PGC1-α signaling and mTOR/eIF2 signaling-dependent pathways. Our findings show for the first time that prolonged energy deprivation induced modulation of mitochondrial metabolism can be observed through minimally invasive measures of leukocyte transcriptome and serum metabolome at systemic level, suggesting that adaptation to energy deficit is broader in humans than previously thought.

Keywords:  diet; exercise; leukocytes; oxidative phosphorylation; ribosomes

DOI:  https://doi.org/10.1096/fj.202002029R
J Geriatr Phys Ther. 2021 Feb 26.

Skeletal Muscle Adaptations Following 80 Weeks of Resistance Exercise in Older Adults.

Ryan M Miller, Debra A Bemben, Michael G Bemben.

BACKGROUND AND PURPOSE: We followed and documented skeletal muscle adaptations from 4 resistance exercise (RE) prescriptions in older adults over the course of a 2-year, 80-week training study.
METHODS: Forty-three older men and women-65.2 (3.5) years, 167.2 (7.5) cm, and 72.5 (14.7) kg-completed one of the following RE prescriptions: high-load 2 days per week (HL2D; n = 12), low-load 2 days per week (LL2D; n = 9), high-load 3 days per week (HL3D, n = 12), or low-load 3 days per week (LL3D, n = 10). High-load prescriptions consisted of 3 sets of 8 repetitions with 80% 1-repetition maximum (1-RM) and low-load prescriptions completed 3 sets of 16 repetitions with 40% 1-RM. Each session consisted of 12 exercises targeting major muscle groups and training loads were adjusted every fifth week to maintain progressive overload. Participants completed 40 weeks of supervised training, had a 2-month break, and then resumed another 40 weeks of supervised training. Bone-free lean body mass (BFLBM) and appendicular lean mass (ALM) were assessed via dual-energy x-ray absorptiometry and muscle cross-sectional area (mCSA) of the rectus femoris with diagnostic ultrasound across the intervention.
RESULTS AND DISCUSSION: Groups responded similarly with significant increases in total strength (54.9%), upper body strength (42.7%), lower body strength (61.5%), and specific strength (50.3%, strength/BFLBM) over 80 weeks (all P < .001). Significant increases for BFLBM (3.0%), ALM (3.5%), and mCSA (48.7%) were also observed (all P ≤ .019). The only difference among groups indicated HL3D displaying significantly greater percent increase than LL2D for ALM (P = .043).
CONCLUSIONS: Resistance exercise performed 2 or 3 days per week with moderate to heavy loads can improve muscle strength and induce small but perhaps clinically significant increases in BFLBM and mCSA in older adults over a 2-year period of supervised training.

DOI: https://doi.org/10.1519/JPT.0000000000000302
J Appl Physiol (1985). 2021 Mar 11.

Fragile bones of elite cyclists: to treat or not to treat?

Luuk Hilkens, Pim Knuiman, Mathieu Heijboer, Robert Kempers, Asker E Jeukendrup, Luc J C van Loon, Jan-Willem van Dijk.



Keywords:  bone; elite cyclists; exercise; nutrition; osteoporosis

DOI:  https://doi.org/10.1152/japplphysiol.01034.2020