Molecular Mechanisms of Exercise and Healthspan

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700
Cells cells	5.1	9.9	2012	17 Days	CHF 2700
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Journal of Molecular Pathology jmp	-	-	2020	26.5 Days	CHF 1000
Muscles muscles	-	-	2022	32 Days	CHF 1000

50 pages, 4279 KiB

Open AccessReview

Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review

by Alexandra K. Mitchell, Rebecca R. Bliss and Frank C. Church

Biomolecules 2024, 14(10), 1241; https://doi.org/10.3390/biom14101241 - 30 Sep 2024

Cited by 3 | Viewed by 4800

Parkinson’s disease (PD) is a prevalent neurodegenerative disease in which treatment often includes an exercise regimen. Exercise is neuroprotective in animal models of PD, and, more recently, human clinical studies have verified exercise’s disease-modifying effect. Aerobic exercise and resistance training improve many of [...] Read more.

Parkinson’s disease (PD) is a prevalent neurodegenerative disease in which treatment often includes an exercise regimen. Exercise is neuroprotective in animal models of PD, and, more recently, human clinical studies have verified exercise’s disease-modifying effect. Aerobic exercise and resistance training improve many of PD’s motor and non-motor symptoms, while neuromotor therapy and stretching/flexibility exercises positively contribute to the quality of life in people with PD. Therefore, understanding the role of exercise in managing this complex disorder is crucial. Exerkines are bioactive substances that are synthesized and released during exercise and have been implicated in several positive health outcomes, including neuroprotection. Exerkines protect neuronal cells in vitro and rodent PD models in vivo. Aerobic exercise and resistance training both increase exerkine levels in the blood, suggesting a role for exerkines in the neuroprotective theory. Many exerkines demonstrate the potential for protecting the brain against pathological missteps caused by PD. Every person (people) with Parkinson’s (PwP) needs a comprehensive exercise plan tailored to their unique needs and abilities. Here, we provide an exercise template to help PwP understand the importance of exercise for treating PD, describe barriers confronting many PwP in their attempt to exercise, provide suggestions for overcoming these barriers, and explore the role of exerkines in managing PD. In conclusion, exercise and exerkines together create a powerful neuroprotective system that should contribute to slowing the chronic progression of PD. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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25 pages, 1779 KiB

Open AccessReview

Myokines May Be the Answer to the Beneficial Immunomodulation of Tailored Exercise—A Narrative Review

by Zheng Lu, Zhuo Wang, Xin-An Zhang and Ke Ning

Biomolecules 2024, 14(10), 1205; https://doi.org/10.3390/biom14101205 - 25 Sep 2024

Cited by 2 | Viewed by 3471

Abstract

Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction [...] Read more.

Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction and the expression of myokines including irisin, IL-6, BDNF, etc. Here, we review nine myokines that are regulated by exercise. These myokines have been shown to be associated with immune responses and to regulate the proliferation, differentiation, and maturation of immune cells and enhance their function, thereby serving to improve the health of the organism. The aim of this article is to review the effects of myokines on intrinsic and adaptive immunity and the important role that exercise plays in them. It provides a theoretical basis for exercise to promote health and provides a potential mechanism for the correlation between muscle factor expression and immunity, as well as the involvement of exercise in body immunity. It also provides the possibility to find a suitable exercise training program for immune system diseases. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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22 pages, 11579 KiB

Open AccessArticle

Exercise Rescues Obesogenic-Related Genes in the Female Hypothalamic Arcuate Nucleus: A Potential Role of miR-211 Modulation

by Kayla Rapps, Asaf Marco, Hilla Pe’er-Nissan, Tatiana Kisliouk, Gabrielle Stemp, Gal Yadid, Aron Weller and Noam Meiri

Int. J. Mol. Sci. 2024, 25(13), 7188; https://doi.org/10.3390/ijms25137188 - 29 Jun 2024

Cited by 1 | Viewed by 1172

Abstract

Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent or combat obesity. This study investigates how voluntary exercise mitigates abnormal gene expression in the hypothalamic arcuate nucleus (ARC) of [...] Read more.

Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent or combat obesity. This study investigates how voluntary exercise mitigates abnormal gene expression in the hypothalamic arcuate nucleus (ARC) of diet-induced obese (DIO) rats. Using a transcriptomic approach, novel genes in the ARC affected by voluntary wheel running were assessed alongside physiology, pharmacology, and bioinformatics analysis to evaluate the role of miR-211 in reversing obesity. Exercise curbed weight gain and fat mass, and restored ARC gene expression. High-fat diet (HFD) consumption can dysregulate satiety/hunger mechanisms in the ARC. Transcriptional clusters revealed that running altered gene expression patterns, including inflammation and cellular structure genes. To uncover regulatory mechanisms governing gene expression in DIO attenuation, we explored miR-211, which is implicated in systemic inflammation. Exercise ameliorated DIO overexpression of miR-211, demonstrating its pivotal role in regulating inflammation in the ARC. Further, in vivo central administration of miR-211-mimic affected the expression of immunity and cell cycle-related genes. By cross-referencing exercise-affected and miR-211-regulated genes, potential candidates for obesity reduction through exercise were identified. This research suggests that exercise may rescue obesity through gene expression changes mediated partially through miR-211. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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20 pages, 2271 KiB

Open AccessArticle

Effects of Treadmill Running at Different Light Cycles in Mice with Metabolic Disorders

by Anna Nikolaevna Zakharova, Kseniya Gennadievna Milovanova, Anna Alekseevna Orlova, Elena Yuryevna Dyakova, Julia Gennadievna Kalinnikova, Olesya Vadimovna Kollantay, Igor Yurievich Shuvalov, Alexander Valerievich Chibalin and Leonid Vladimirovich Kapilevich

Int. J. Mol. Sci. 2023, 24(20), 15132; https://doi.org/10.3390/ijms242015132 - 13 Oct 2023

Cited by 3 | Viewed by 2314

Abstract

Type 2 diabetes mellitus accounts for about 90% of cases of diabetes and is considered one of the most important problems of our time. Despite a significant number of studies on glucose metabolism, the molecular mechanisms of its regulation in health and disease [...] Read more.

Type 2 diabetes mellitus accounts for about 90% of cases of diabetes and is considered one of the most important problems of our time. Despite a significant number of studies on glucose metabolism, the molecular mechanisms of its regulation in health and disease remain insufficiently studied. That is why non-drug treatment of metabolic disorders is of great relevance, including physical activity. Metabolic changes under the influence of physical activity are very complex and are still difficult to understand. This study aims to deepen the understanding of the effect of physical exercise on metabolic changes in mice with diabetes mellitus. We studied the effect of forced treadmill running on body weight and metabolic parameters in mice with metabolic disorders. We developed a high-fat-diet-induced diabetic model of metabolic disorders. We exposed mice to forced treadmill running for 4 weeks. We determined glucose and insulin levels in the blood plasma biochemically and analyzed Glut-4 and citrate synthase in M. gastrocnemius muscle tissue using Western blotting. The research results show that daily treadmill running has different effects on different age groups of mice with metabolic disorders. In young-age animals, forced running has a more pronounced effect on body weight. At week 12, young obese mice had a 17% decrease in body weight. Body weight did not change in old mice. Moreover, at weeks 14 and 16, the decrease in body weight was more significant in the young mice (by 17%) compared to the old mice (by 6%) (p < 0.05). In older animals, it influences the rate of glucose uptake. At 60 min, the blood glucose in the exercised older mice decreased to 14.46 mmol/L, while the glucose concentration in the non-exercised group remained at 17 mmol/L. By 120 min, in mice subjected to exercise, the blood glucose approached the initial value (6.92 mmol/L) and amounted to 8.35 mmol/L. In the non-exercised group, this difference was 45%. The effects of physical activity depend on the time of day. The greater effect is observed when performing shift training or exercise during the time when animals are passive (light phase). In young mice, light phase training had a significant effect on increasing the content of Glut-4 in muscle tissue (84.3 ± 11.3%, p < 0.05 with control group—59.3 ± 7.8%). In aged mice, shift training caused an increase in the level of Glut-4 in muscle tissue (71.3 ± 4.1%, p < 0.05 with control group—56.4 ± 10,9%). In the group of aged mice, a lower CS level was noticed in all groups in comparison with young mice. It should also be noted that we observed that CS increased during exercise in the group of young mice, especially during light phase training. The CS content in the light phase subgroup (135.8 ± 7.0%) was higher than in the dark phase subgroup (113.3 ± 7.7%) (p = 0.0006). The CS decreased in aged chow-fed mice and increased in the high-fat-fed group. The CS content in the chow diet group (58.2 ± 5.0%) was 38% lower than in the HFD group (94.9 ± 8.8%). Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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14 pages, 1408 KiB

Open AccessFeature PaperArticle

Sedentary Behavior Impacts on the Epigenome and Transcriptome: Lessons from Muscle Inactivation in Drosophila Larvae

by Avivit Brener, Dana Lorber, Adriana Reuveny, Hila Toledano, Lilach Porat-Kuperstein, Yael Lebenthal, Eviatar Weizman, Tsviya Olender and Talila Volk

Cells 2023, 12(19), 2333; https://doi.org/10.3390/cells12192333 - 22 Sep 2023

Viewed by 2031

Abstract

The biological mechanisms linking sedentary lifestyles and metabolic derangements are incompletely understood. In this study, temporal muscle inactivation in Drosophila larvae carrying a temperature-sensitive mutation in the shibire (shi¹) gene was induced to mimic sedentary behavior during early life and [...] Read more.

The biological mechanisms linking sedentary lifestyles and metabolic derangements are incompletely understood. In this study, temporal muscle inactivation in Drosophila larvae carrying a temperature-sensitive mutation in the shibire (shi¹) gene was induced to mimic sedentary behavior during early life and study its transcriptional outcome. Our findings indicated a significant change in the epigenetic profile, as well as the genomic profile, of RNA Pol II binding in the inactive muscles relative to control, within a relatively short time period. Whole-genome analysis of RNA-Pol II binding to DNA by muscle-specific targeted DamID (TaDa) protocol revealed that muscle inactivity altered Pol II binding in 121 out of 2010 genes (6%), with a three-fold enrichment of genes coding for lncRNAs. The suppressed protein-coding genes included genes associated with longevity, DNA repair, muscle function, and ubiquitin-dependent proteostasis. Moreover, inducing muscle inactivation exerted a multi-level impact upon chromatin modifications, triggering an altered epigenetic balance of active versus inactive marks. The downregulated genes in the inactive muscles included genes essential for muscle structure and function, carbohydrate metabolism, longevity, and others. Given the multiple analogous genes in Drosophila for many human genes, extrapolating our findings to humans may hold promise for establishing a molecular link between sedentary behavior and metabolic diseases. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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7 pages, 227 KiB

Open AccessCommentary

Physical Exercise and Appetite Regulation: New Insights

by Lorenzo Caruso, Enrico Zauli and Mauro Vaccarezza

Biomolecules 2023, 13(8), 1170; https://doi.org/10.3390/biom13081170 - 27 Jul 2023

Cited by 3 | Viewed by 4325

Abstract

Physical exercise is considered an important physiological intervention able to prevent cardiovascular diseases, obesity, and obesity-related cardiometabolic imbalance. Nevertheless, basic molecular mechanisms that govern the metabolic benefits of physical exercise are poorly understood. Recent data unveil new mechanisms that potentially explain the link [...] Read more.

Physical exercise is considered an important physiological intervention able to prevent cardiovascular diseases, obesity, and obesity-related cardiometabolic imbalance. Nevertheless, basic molecular mechanisms that govern the metabolic benefits of physical exercise are poorly understood. Recent data unveil new mechanisms that potentially explain the link between exercise, feeding suppression, and obesity. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

14 pages, 2372 KiB

Open AccessArticle

Endurance Exercise-Induced Fgf21 Promotes Skeletal Muscle Fiber Conversion through TGF-β1 and p38 MAPK Signaling Pathway

by Xiaomao Luo, Huiling Zhang, Xiaorui Cao, Ding Yang, Yi Yan, Jiayin Lu, Xiaonan Wang and Haidong Wang

Int. J. Mol. Sci. 2023, 24(14), 11401; https://doi.org/10.3390/ijms241411401 - 13 Jul 2023

Cited by 10 | Viewed by 3500

Abstract

Fgf21 has been identified as playing a regulatory role in muscle growth and function. Although the mechanisms through which endurance training regulates skeletal muscle have been widely studied, the contribution of Fgf21 remains poorly understood. Here, muscle size and function were measured, and [...] Read more.

Fgf21 has been identified as playing a regulatory role in muscle growth and function. Although the mechanisms through which endurance training regulates skeletal muscle have been widely studied, the contribution of Fgf21 remains poorly understood. Here, muscle size and function were measured, and markers of fiber type were evaluated using immunohistochemistry, immunoblots, or qPCR in endurance-exercise-trained wild-type and Fgf21 KO mice. We also investigated Fgf21-induced fiber conversion in C2C12 cells, which were incubated with lentivirus and/or pathway inhibitors. We found that endurance exercise training enhanced the Fgf21 levels of liver and GAS muscle and exercise capacity and decreased the distribution of skeletal muscle fiber size, and fast-twitch fibers were observed converting to slow-twitch fibers in the GAS muscle of mice. Fgf21 promoted the markers of fiber-type transition and eMyHC-positive myotubes by inhibiting the TGF-β1 signaling axis and activating the p38 MAPK signaling pathway without apparent crosstalk. Our findings suggest that the transformation and function of skeletal muscle fiber types in response to endurance training could be mediated by Fgf21 and its downstream signaling pathways. Our results illuminate the mechanisms of Fgf21 in endurance-exercise-induced fiber-type conversion and suggest a potential use of Fgf21 in improving muscle health and combating fatigue. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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20 pages, 3047 KiB

Open AccessArticle

Skeletal Muscle MicroRNA Patterns in Response to a Single Bout of Exercise in Females: Biomarkers for Subsequent Training Adaptation?

by Alexandra Grieb, Angelika Schmitt, Annunziata Fragasso, Manuel Widmann, Felipe Mattioni Maturana, Christof Burgstahler, Gunnar Erz, Philipp Schellhorn, Andreas M. Nieß and Barbara Munz

Biomolecules 2023, 13(6), 884; https://doi.org/10.3390/biom13060884 - 24 May 2023

Cited by 2 | Viewed by 2170

Abstract

microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (n = 6) before and after a single submaximal bout [...] Read more.

microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (n = 6) before and after a single submaximal bout of endurance exercise (‘reference training’). Subsequently, participants were subjected to a structured training program, consisting of six weeks of moderate-intensity continuous endurance training (MICT) and six weeks of high-intensity interval training (HIIT) in randomized order. In vastus lateralis muscle, we found significant downregulation of myomiRs, specifically miR-1, 133a-3p, and -5p, -133b, and -499a-5p. Similarly, exercise-associated miRs-23a-3p, -378a-5p, -128-3p, -21-5p, -107, -27a-3p, -126-3p, and -152-3p were significantly downregulated, whereas miR-23a-5p was upregulated. Furthermore, in an untargeted approach for differential expression in response to acute exercise, we identified n = 35 miRs that were downregulated and n = 20 miRs that were upregulated by factor 4.5 or more. Remarkably, KEGG pathway analysis indicated central involvement of this set of miRs in fatty acid metabolism. To reproduce these data in a larger cohort of all-female subjects (n = 29), qPCR analysis was carried out on n = 15 miRs selected from the microarray, which confirmed their differential expression. Furthermore, the acute response, i.e., the difference between miR concentrations before and after the reference training, was correlated with changes in maximum oxygen uptake (V̇O₂max) in response to the training program. Here, we found that miRs-199a-3p and -19b-3p might be suitable acute-response candidates that correlate with individual degrees of training adaptation in females. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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18 pages, 1279 KiB

Open AccessArticle

Exercise-Induced Alternations of Adiponectin, Interleukin-8 and Indicators of Carbohydrate Metabolism in Males with Metabolic Syndrome

by Karol Makiel, Agnieszka Suder, Aneta Targosz, Marcin Maciejczyk and Alon Haim

Biomolecules 2023, 13(5), 852; https://doi.org/10.3390/biom13050852 - 18 May 2023

Cited by 8 | Viewed by 3266

Abstract

Adiponectin (ADIPO) and interleukin-8 (IL-8) are proteins that play a significant, albeit opposing, role in metabolic syndrome (MetS). The reported data on the effect of physical activity on the levels of these hormones in the population of people with MetS are conflicting. The [...] Read more.

Adiponectin (ADIPO) and interleukin-8 (IL-8) are proteins that play a significant, albeit opposing, role in metabolic syndrome (MetS). The reported data on the effect of physical activity on the levels of these hormones in the population of people with MetS are conflicting. The aim of the study was to evaluate the changes in hormone concentrations, insulin-resistance indices and body composition after two types of training. The study included 62 men with MetS (age 36.6 ± 6.9 years, body fat [BF] = 37.53 ± 4.5%), randomly assigned to: an experimental group EG1 (n = 21) with aerobic exercise intervention, an experimental group EG2 (n = 21) with combined aerobic and resistance exercise intervention, both for 12 weeks, and a control group CG (n = 20) without interventions. Anthropometric measurements and body composition (fat-free mass [FFM], gynoid body fat [GYNOID]), as well as a biochemical blood analysis (adiponectin [ADIPO], interleukin-8 [IL-8], homeostatic model assessment—adiponectin (HOMA-AD) and homeostatic model assessment—triglycerides (HOMA-TG) were performed at baseline, and at 6 and 12 weeks of intervention and 4 weeks after the intervention (follow-up). Intergroup (between groups) and intragroup (within each group) changes were statistically evaluated. In the experimental groups EG1 and EG2, no significant changes were observed in the ADIPO concentration, but a decrease of GYNOID and insulin-resistance indices was confirmed. The aerobic training led to favorable changes in IL-8 concentration. The use of combined resistance and aerobic training led to improved body composition, decreased waist circumference and better insulin-resistance indices in men with MetS. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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11 pages, 3978 KiB

Open AccessEditor’s ChoiceArticle

Both Acute and Consecutive Days of Formoterol Stimulation Influence Myogenic, Mitochondrial, and myomiR Gene Expression in Human Skeletal Muscle Cells

by Ryan A. Gordon, Emily L. Zumbro, Gena D. Guerin, Matthew L. Sokoloski, Vic Ben-Ezra, Christopher S. Brower, Rhett B. Rigby and Anthony A. Duplanty

Muscles 2023, 2(1), 86-96; https://doi.org/10.3390/muscles2010008 - 22 Feb 2023

Viewed by 2327

Abstract

Skeletal muscle physiology is regulated by microRNA that are localized within skeletal muscle (myomiRs). This study investigated how the expression of myomiRs and genes regulating skeletal muscle mass and myogenesis are influenced in response to acute and consecutive days of exercise-related signaling using [...] Read more.

Skeletal muscle physiology is regulated by microRNA that are localized within skeletal muscle (myomiRs). This study investigated how the expression of myomiRs and genes regulating skeletal muscle mass and myogenesis are influenced in response to acute and consecutive days of exercise-related signaling using the exercise mimetic, formoterol, in vitro. Human skeletal muscle cells were proliferated and differentiated for 6 days. Experimental conditions included: (a) control, (b) acute formoterol stimulation (AFS), and (c) consecutive days of formoterol stimulation (CFS). For AFS, myotubes were treated with 30 nM of formoterol for three hours on day 6 of differentiation, and this was immediately followed by RNA extraction. For CFS, myotubes were treated with 30 nM of formoterol for three hours on two or three consecutive days, with RNA extracted immediately following the final three-hour formoterol treatment. We observed increased myomiR expression for both AFS and CFS. AFS appeared to promote myogenesis, but this effect was lost with CFS. Additionally, we observed increased expression of genes involved in metabolism, mitochondrial biogenesis, and muscle protein degradation in response to AFS. myomiR and gene expression appear to be sensitive to acute and long-term exercise-related stimuli, and this likely contributes to the regulation of skeletal muscle mass. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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