bims-exemet 2021-08-08 papers

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

J Appl Physiol (1985). 2021 Aug 05.

Acute endurance exercise stimulates circulating levels of mitochondrial derived peptides in humans.

Ferdinand von Walden, Rodrigo Fernandez-Gonzalo, Jessica Maria Norrbom, Eric B Emanuelsson, Vandre C Figueiredo, Eva-Karin Gidlund, Lena Norrbrand, Chang Liu, Philip Sandström, Björn Hansson, Junxiang Wan, Pinchas Cohen, Björn Alkner.

Mitochondrial derived peptides (MDPs) humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis and metabolism. Circulating levels of MDPs are altered in chronic diseases such as diabetes type 2 and chronic kidney disease. Whether acute resistance (RE) or endurance (EE) exercise modulates circulating levels of HN and MOTS-c in humans is unknown. Following familiarization, subjects were randomized to EE (n=10, 45 min cycling at 70% of estimated VO2max), RE (n=10, 4 sets x 7RM, leg press and knee extension), or control (CON, n=10). Skeletal muscle biopsies and blood samples were collected before and at 30 minutes and 3 hours following exercise. Plasma concentration of HN and MOTS-c, skeletal muscle MOTS-c as well as gene expression of exercise related genes were analyzed. Acute EE and RE promoted changes in skeletal muscle gene expression typically seen in response to each exercise modality (c-Myc, 45S pre-rRNA, PGC-1α-total and PGC-1α-ex1b). At rest, circulating levels of HN were positively correlated to MOTS-c levels and age. Plasma levels of MDPs were not correlated to fitness outcomes (VO2max, leg strength or muscle mitochondrial (mt) DNA copy number). Circulating levels of HN were significantly elevated by acute EE but not RE. MOTS-C levels showed a trend to increase after EE. These results indicate that plasma MDP levels are not related to fitness status but that acute EE increases circulating levels of MDPs, in particular HN.

Keywords: Skeletal muscle; exercise; humanin; mitochondria; mots-c

DOI: https://doi.org/10.1152/japplphysiol.00706.2019

Trends Endocrinol Metab. 2021 Jul 28. pii: S1043-2760(21)00156-9. [Epub ahead of print]

Is high-intensity interval training harmful to health?

Niklas Joisten, Sebastian Gehlert, Philipp Zimmer.

High-intensity interval training (HIIT) is a common method to increase performance and promote health in elite sports, rehabilitation, and disease prevention. Flockhart et al. suggest a limit of HIIT above which detrimental effects on metabolic health emerge. We put these findings into context and assess the evidence that HIIT might be harmful.

Keywords: HIIT; exercise; glucose tolerance; metabolism; mitochondria

DOI: https://doi.org/10.1016/j.tem.2021.07.003

FASEB J. 2021 Sep;35(9): e21830

Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.

Craig R G Willis, Iain J Gallagher, Daniel J Wilkinson, Matthew S Brook, Joseph J Bass, Bethan E Phillips, Kenneth Smith, Timothy Etheridge, Tanner Stokes, Chris McGlory, Stefan H M Gorissen, Nathaniel J Szewczyk, Stuart M Phillips, Philip J Atherton.

Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3 mL.kg-1 ), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.

Keywords: atrophy; disuse; gene network analysis; muscle protein synthesis; skeletal muscle

DOI: https://doi.org/10.1096/fj.202100276RR

J Cachexia Sarcopenia Muscle. 2021 Aug 02.

Modified UCN2 peptide treatment improves skeletal muscle mass and function in mouse models of obesity-induced insulin resistance.

Melissa L Borg, Julie Massart, Thais De Castro Barbosa, Adrià Archilla-Ortega, Jonathon A B Smith, Johanna T Lanner, Jorge Alsina-Fernandez, Benjamin Yaden, Alexander E Culver, Håkan K R Karlsson, Joseph T Brozinick, Juleen R Zierath.

BACKGROUND: Type 2 diabetes and obesity are often seen concurrently with skeletal muscle wasting, leading to further derangements in function and metabolism. Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass. The aim of this study was to investigate the effects of modified UCN2 peptides as a pharmaceutical therapy to counteract the loss of skeletal muscle mass associated with obesity and casting immobilization.
METHODS: High-fat-fed mice (C57Bl/6J; 26 weeks old) and ob/ob mice (11 weeks old) were injected daily with a PEGylated (Compound A) and non-PEGylated (Compound B) modified human UCN2 at 0.3 mg/kg subcutaneously for 14 days. A separate group of chow-fed C57Bl/6J mice (12 weeks old) was subjected to hindlimb cast immobilization and, after 1 week, received daily injections with Compound A. In vivo functional tests were performed to measure protein synthesis rates and skeletal muscle function. Ex vivo functional and molecular tests were performed to measure contractile force and signal transduction of catabolic and anabolic pathways in skeletal muscle.
RESULTS: Skeletal muscles (extensor digitorum longus, soleus, and tibialis anterior) from high-fat-fed mice treated with Compound A were ~14% heavier than muscles from vehicle-treated mice. Chronic treatment with modified UCN2 peptides altered the expression of structural genes and transcription factors in skeletal muscle in high-fat diet-induced obesity including down-regulation of Trim63 and up-regulation of Nr4a2 and Igf1 (P < 0.05 vs. vehicle). Signal transduction via both catabolic and anabolic pathways was increased in tibialis anterior muscle, with increased phosphorylation of ribosomal protein S6 at Ser235/236 , FOXO1 at Ser256 , and ULK1 at Ser317 , suggesting that UCN2 treatment modulates protein synthesis and degradation pathways (P < 0.05 vs. vehicle). Acutely, a single injection of Compound A in drug-naïve mice had no effect on the rate of protein synthesis in skeletal muscle, as measured via the surface sensing of translation method, while the expression of Nr4a3 and Ppargc1a4 was increased (P < 0.05 vs. vehicle). Compound A treatment prevented the loss of force production from disuse due to casting. Compound B treatment increased time to fatigue during ex vivo contractions of fast-twitch extensor digitorum longus muscle. Compound A and B treatment increased lean mass and rates of skeletal muscle protein synthesis in ob/ob mice.
CONCLUSIONS: Modified human UCN2 is a pharmacological candidate for the prevention of the loss of skeletal muscle mass associated with obesity and immobilization.

Keywords: Diabetes; Exercise; Insulin resistance; Muscle wasting; Obesity; Therapy

DOI: https://doi.org/10.1002/jcsm.12746

Nat Commun. 2021 Aug 06. 12(1): 4773

Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function.

L Grevendonk, N J Connell, C McCrum, C E Fealy, L Bilet, Y M H Bruls, J Mevenkamp, V B Schrauwen-Hinderling, J A Jörgensen, E Moonen-Kornips, G Schaart, B Havekes, J de Vogel-van den Bosch, M C E Bragt, K Meijer, P Schrauwen, J Hoeks.

The relationship between the age-associated decline in mitochondrial function and its effect on skeletal muscle physiology and function remain unclear. In the current study, we examined to what extent physical activity contributes to the decline in mitochondrial function and muscle health during aging and compared mitochondrial function in young and older adults, with similar habitual physical activity levels. We also studied exercise-trained older adults and physically impaired older adults. Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle.

DOI: https://doi.org/10.1038/s41467-021-24956-2

Cell Metab. 2021 Jul 30. pii: S1550-4131(21)00331-4. [Epub ahead of print]

Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells.

Zheng Fan, Guillermo Turiel, Raphaela Ardicoglu, Moheb Ghobrial, Evi Masschelein, Tea Kocijan, Jing Zhang, Ge Tan, Gillian Fitzgerald, Tatiane Gorski, Abdiel Alvarado-Diaz, Paola Gilardoni, Christopher M Adams, Bart Ghesquière, Katrien De Bock.

Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.

Keywords: amino acid metabolism; endothelial heterogeneity; endothelial metabolism; exercise; muscle angiogenesis; single-cell RNA-seq

DOI: https://doi.org/10.1016/j.cmet.2021.07.015

Obesity (Silver Spring). 2021 Aug 02.

A single bout of exercise improves vascular insulin sensitivity in adults with obesity.

Emily M Heiston, Zhenqi Liu, Anna Ballantyne, Sibylle Kranz, Steven K Malin.

OBJECTIVE: This crossover study explored the impact of a single bout of exercise on insulin-stimulated responses in conduit arteries and capillaries.
METHODS: Twelve sedentary adults (49.5 [7.8] years; maximal oxygen consumption [VO2 max]: 23.7 [5.4] mL/kg/min) with obesity (BMI 34.5 [4.3] kg/m2 ) completed a control and exercise bout (70% VO2 max to expend 400 kcal). Sixteen hours later, participants underwent a 2-hour euglycemic-hyperinsulinemic clamp (90 mg/dL; 40 mU/m2 /min) to determine vascular and metabolic insulin sensitivity. Endothelial and capillary functions were assessed by brachial artery flow-mediated dilation and contrast-enhanced ultrasound, respectively. Metabolized glucose infusion rate, substrate oxidation (indirect calorimetry), nonoxidative glucose disposal (NOGD), and inflammation were also determined.
RESULTS: Exercise increased insulin-stimulated preocclusion diameter (p = 0.01) and microvascular blood flow (condition effect: p = 0.04) compared with control. Furthermore, exercise improved metabolic insulin sensitivity by 21%, which paralleled rises in NOGD (p = 0.05) and decreases in soluble receptors for advanced glycation end products (condition effect: p = 0.01). Interestingly, changes in NOGD were related to increased insulin-stimulated microvascular blood flow (r = 0.57, p = 0.05).
CONCLUSIONS: A single bout of exercise increases vascular insulin sensitivity in adults with obesity. Additional work is needed to determine vascular responses following different doses of exercise in order to design lifestyle prescriptions for reducing chronic disease risk.

DOI: https://doi.org/10.1002/oby.23229