Abstract 15255: Statins Augment Circulating MicroRNA-499-5p Release With Muscle Contraction and Aerobic Exercise

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Pil-Ki Min ◽  
Joseph Park ◽  
Stephanie Isaacs ◽  
Beth A Taylor ◽  
Paul D Thompson ◽  
...  
Keyword(s):  
Muscle Contraction ◽  
Muscle Injury ◽  
Fold Change ◽  
C2c12 Myotubes ◽  
Circulating Microrna ◽  
Cultured Myotubes ◽  
Exercise Induced ◽  
Statin Use

Background: Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. Objectives: We examined the relationships among statin exposure, in vitro and in vivo muscle contraction, and candidate circulating myomiRs expression. Methods: We measured plasma levels of the myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206 and c-miR-499-5p, from 28 statin-using and 28 non-statin using runners before (PRE), immediately after (FINISH), and 24 hours after a 42 km footrace (POST-24). We subsequently used contracting mouse C2C12 cultured myotubes with and without statin exposure to compare intracellular and extracellular expression of these molecules. Fold-changes of microRNAs are presented as median [interquartile range]. Results: In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH in both groups, but c-miR-499-5p increased in statin users at the POST-24 time point compared to PRE [2.9 (1.3, 8.6) vs. 1.0 fold change, p <0.001] and to non-statin using runners [2.9 (1.3, 8.6) vs. 1.4 (0.9, 3.2) fold change, p < 0.05]. In cultured C2C12 myotubes, intracellular levels of candidate myomiRs remained stable except for modest declines of miR-1 and miR-206 with isolated myotube contraction (carbachol exposure) or simultaneous statin and myotube contraction. Extracellular miR-1, 133a, and 206 increased with contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated contraction but increased with contraction + statin [4.8 (1.9, 8.1) vs. 1.0 (0.7, 1.5) fold change, p < 0.05 vs. control]. Conclusions: Statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage.

scholarly journals Influence of statins on distinct circulating microRNAs during prolonged aerobic exercise

2016 ◽  
Vol 120 (6) ◽  
pp. 711-720 ◽  
Author(s):  
Pil-Ki Min ◽  
Joseph Park ◽  
Stephanie Isaacs ◽  
Beth A. Taylor ◽  
Paul D. Thompson ◽  
...  
Keyword(s):  
Muscle Contraction ◽  
Muscle Injury ◽  
C2c12 Myotubes ◽  
Circulating Microrna ◽  
Extracellular Release ◽  
Boston Marathon ◽  
Exercise Induced ◽  
Statin Use

Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. We examined the relationships between statin exposure, in vitro and in vivo muscle contraction, and expression of candidate circulating myomiRs. We measured plasma levels of myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206, and c-miR-499-5p from 28 statin-using and 28 nonstatin-using runners before (PRE), immediately after (FINISH), and 24 h after they ran a 42-km footrace (the 2011 Boston marathon) (POST-24). To examine these cellular-regulation myomiRs, we used contracting mouse C2C12 myotubes in culture with and without statin exposure to compare intracellular and extracellular expression of these molecules. In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH but increased at POST-24 among statin users compared with PRE and runners who did not take statins. In cultured C2C12 myotubes, extracellular c-miR-1, c-miR-133a, and c-miR-206 were significantly increased by muscle contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated carbachol exposure but it was increased when muscle contraction was combined with statin exposure. In summary, we found that statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. Thus c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage.

scholarly journals MyD88 Is Not Required for Muscle Injury-Induced Endochondral Heterotopic Ossification in a Mouse Model of Fibrodysplasia Ossificans Progressiva

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 630
Author(s):  
Huili Lyu ◽  
Cody M. Elkins ◽  
Jessica L. Pierce ◽  
C. Henrique Serezani ◽  
Daniel S. Perrien
Keyword(s):  
Heterotopic Ossification ◽  
Muscle Injury ◽  
Cell Types ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Inflammatory Signaling ◽  
Conditional Deletion ◽  
Pathway Crosstalk ◽  
Multiple Cell

Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple cell types, suggesting the importance of pathway crosstalk in EHO and FOP. Toll-like receptors (TLRs) and IL-1 receptors mediate many of the earliest injury-induced inflammatory signals largely via MyD88-dependent pathways. Thus, the hypothesis that MyD88-dependent signaling is required for EHO was tested in vitro and in vivo using global or Pdgfrα-conditional deletion of MyD88 in FOP mice. As expected, IL-1β or LPS synergistically increased Activin A (ActA)-induced phosphorylation of Smad 1/5 in fibroadipoprogenitors (FAPs) expressing Alk2R206H. However, conditional deletion of MyD88 in Pdgfrα-positive cells of FOP mice did not significantly alter the amount of muscle injury-induced EHO. Even more surprisingly, injury-induced EHO was not significantly affected by global deletion of MyD88. These studies demonstrate that MyD88-dependent signaling is dispensable for injury-induced EHO in FOP mice.

scholarly journals ADP-ribosylation of integrin α7 modulates the binding of integrin α7β1 to laminin

2004 ◽  
Vol 385 (1) ◽  
pp. 309-317 ◽  
Author(s):  
Zhefeng ZHAO ◽  
Joanna GRUSZCZYNSKA-BIEGALA ◽  
Anna ZOLKIEWSKA
Keyword(s):  
C2c12 Myotubes ◽  
Post Translational Modification ◽  
Integrin Β1 ◽  
Adp Ribosylation ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
C2c12 Skeletal Muscle Cells ◽  
Adp Ribosyltransferase

The extracellular domain of integrin α7 is ADP-ribosylated by an arginine-specific ecto-ADP-ribosyltransferase after adding exogenous NAD+ to intact C2C12 skeletal muscle cells. The effect of ADP-ribosylation on the structure or function of integrin α7β1 has not been explored. In the present study, we show that ADP-ribosylation of integrin α7 takes place exclusively in differentiated myotubes and that this post-translational modification modulates the affinity of α7β1 dimer for its ligand, laminin. ADP-ribosylation in the 37-kDa ‘stalk’ region of α7 that takes place at micromolar NAD+ concentrations increases the binding of the α7β1 dimer to laminin. Increased in vitro binding of integrin α7β1 to laminin after ADP-ribosylation of the 37-kDa fragment of α7 requires the presence of Mn2+ and it is not observed in the presence of Mg2+. In contrast, ADP-ribosylation of the 63-kDa N-terminal region comprising the ligand-binding site of α7 that occurs at approx. 100 μM NAD+ inhibits the binding of integrin α7β1 to laminin. Furthermore, incubation of C2C12 myotubes with NAD+ increases the expression of an epitope on integrin β1 subunit recognized by monoclonal antibody 9EG7. We discuss our results based on the current models of integrin activation. We also hypothesize that ADP-ribosylation may represent a mechanism of regulation of integrin α7β1 function in myofibres in vivo when the continuity of the membrane is compromised and NAD+ is available as a substrate for ecto-ADP-ribosylation.

scholarly journals Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Kimito Kawahata ◽  
Dengli Wang ◽  
Masahiro Nishibori ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Muscle Cell ◽  
Muscle Injury ◽  
Fas Ligand ◽  
Muscle Fibers ◽  
Inflammatory Molecules

AbstractMuscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

Reversal of the exercise-induced increase in muscle permeability to glucose

1987 ◽  
Vol 253 (4) ◽  
pp. E331-E335 ◽  
Author(s):  
D. A. Young ◽  
H. Wallberg-Henriksson ◽  
M. D. Sleeper ◽  
J. O. Holloszy
Keyword(s):  
Protein Synthesis ◽  
Glucose Transport ◽  
Glycogen Synthesis ◽  
Carbohydrate Restriction ◽  
Rat Serum ◽  
Low Concentration ◽  
Carbohydrate Feeding ◽  
Exercise Induced

Exercise is associated with an increase in permeability of muscle to glucose that reverses slowly (h) in fasting rats during recovery. Previous studies showed that carbohydrate feeding speeds and carbohydrate restriction slows reversal of the exercise-induced increase in glucose uptake. This study was designed to evaluate the roles of glucose transport, glycogen synthesis, and protein synthesis in the reversal process in rat epitrochlearis muscle. In contrast to recovery in vivo, when muscles were incubated without insulin in vitro, the exercise-induced increase in muscle permeability to sugar reversed rapidly regardless of whether glucose transport or glycogen synthesis occurred. Inhibition of protein synthesis did not prevent the reversal. Addition of 33% rat serum or a low concentration of insulin to the incubation medium markedly slowed reversal in vitro. We conclude that 1) prolonged persistence of the increased permeability of mammalian muscle to glucose after exercise requires a low concentration of insulin, and 2) reversal of the increase in permeability does not require glucose transport, glycogen synthesis, or protein synthesis.

Myogenic mechanism for peristalsis in the cat esophagus

1999 ◽  
Vol 277 (2) ◽  
pp. G306-G313 ◽  
Author(s):  
Harold G. Preiksaitis ◽  
Nicholas E. Diamant
Keyword(s):  
Muscle Contraction ◽  
Slow Wave ◽  
Circular Muscle ◽  
Smooth Muscle Contraction ◽  
Slow Waves ◽  
Mechanical Activity ◽  
Control Mechanisms ◽  
Slow Wave Oscillations

A myogenic control system (MCS) is a fundamental determinant of peristalsis in the stomach, small bowel, and colon. In the esophagus, attention has focused on neuronal control, the potential for a MCS receiving less attention. The myogenic properties of the cat esophagus were studied in vitro with and without nerves blocked by 1 μM TTX. Muscle contraction was recorded, while electrical activity was monitored by suction electrodes. Spontaneous, nonperistaltic, electrical, and mechanical activity was seen in the longitudinal muscle and persisted after TTX. Spontaneous circular muscle activity was minimal, and peristalsis was not observed without pharmacological activation. Direct electrical stimulation (ES) in the presence of bethanechol or tetraethylammonium chloride (TEA) produced slow-wave oscillations and spike potentials accompanying smooth muscle contraction that progressed along the esophagus. Increased concentrations of either drug in the presence of TTX produced slow waves and spike discharges, accompanied by peristalsis in 5 of 8 TEA- and 2 of 11 bethanechol-stimulated preparations without ES. Depolarization of the muscle by increasing K+ concentration also produced slow waves but no peristalsis. We conclude that the MCS in the esophagus requires specific activation and is manifest by slow-wave oscillations of the membrane potential, which appear to be necessary, but are not sufficient for myogenic peristalsis. In vivo, additional control mechanisms are likely supplied by nerves.

Effects of exercise on endothelium and endothelium/smooth muscle cross talk: role of exercise-induced hemodynamics

2011 ◽  
Vol 111 (1) ◽  
pp. 311-320 ◽  
Author(s):  
S. C. Newcomer ◽  
Dick H. J. Thijssen ◽  
D. J. Green
Keyword(s):  
Physical Activity ◽  
Shear Stress ◽  
Wall Stress ◽  
Beneficial Effects ◽  
Exercise Induced ◽  
Response To Exercise ◽  
And Training

Physical activity, exercise training, and fitness are associated with decreased cardiovascular risk. In the context that a risk factor “gap” exists in the explanation for the beneficial effects of exercise on cardiovascular disease, it has recently been proposed that exercise generates hemodynamic stimuli which exert direct effects on the vasculature that are antiatherogenic. In this review we briefly introduce some of the in vitro and in vivo evidence relating exercise hemodynamic modulation and vascular adaptation. In vitro data clearly demonstrate the importance of shear stress as a potential mechanism underlying vascular adaptations associated with exercise. Supporting this is in vivo human data demonstrating that exercise-mediated shear stress induces localized impacts on arterial function and diameter. Emerging evidence suggests that exercise-related changes in hemodynamic stimuli other than shear stress may also be associated with arterial remodeling. Taken together, in vitro and in vivo data strongly imply that hemodynamic influences combine to orchestrate a response to exercise and training that regulates wall stress and peripheral vascular resistance and contributes to the antiatherogenic impacts of physical activity, fitness, and training.

Exogenous L-lactate promotes astrocyte plasticity but is not sufficient for enhancing striatal synaptogenesis or motor behavior in mice

2020 ◽  
Author(s):  
Adam J. Lundquist ◽  
Tyler J. Gallagher ◽  
Giselle M. Petzinger ◽  
Michael W. Jakowec
Keyword(s):  
Motor Behavior ◽  
Early Gene ◽  
Specific Gene ◽  
Motor Circuits ◽  
Specific Manner ◽  
Primary Astrocytes ◽  
Exercise Induced ◽  
The Brain

AbstractL-lactate is an energetic and signaling molecule that is key to the metabolic and neuroplastic connection between astrocytes and neurons and may be involved in exercise-induced neuroplasticity. This study sought to explore the role of L-lactate in astrocyte reactivity and neuroplasticity. Using in vitro cultures of primary astrocytes, we show L-lactate increased expression of plasticity-related genes, including neurotrophic factors, Bdnf, Gdnf, Cntf and the immediate early gene cFos. L-lactate’s promotion of neurotrophic factor expression may be mediated in part by the lactate receptor HCAR1 since application of the HCAR1 agonist 3,5-DHBA also increased expression of Bdnf in primary astrocytes. In vivo L-lactate administration to healthy mice caused a similar increase in the expression of plasticity-related genes as well as increased astrocyte morphological complexity in a region-specific manner, with increased astrocytic response found in the striatum but not the ectorhinal cortex, regions of the brain where increases in regional cerebral blood flow are increased or unaltered, respectively, with motor behavior. Additionally, L-lactate administration did not cause synaptogenesis or improve motor behavior based on the latency to fall on the accelerating rotarod, suggesting that L-lactate administration can initiate astrocyte-specific gene expression, but the activation of motor circuits is necessary to initiate striatal neuroplasticity. These results suggest that peripheral L-lactate is likely an important molecular component of exercise-induced neuroplasticity by acting in an astrocyte-specific manner to prime the brain for neuroplasticity.

Effect of prior immobilization on muscular glucose clearance in resting and running rats

1988 ◽  
Vol 255 (4) ◽  
pp. E456-E462 ◽  
Author(s):  
J. Vissing ◽  
T. Ohkuwa ◽  
T. Ploug ◽  
H. Galbo
Keyword(s):  
Separate Determination ◽  
Mediated Action ◽  
Glucose Clearance ◽  
Red Muscle ◽  
Exercise Induced ◽  
And Control ◽  
Uptake And Metabolism

In vitro studies have shown that prior disuse impairs the glucose clearance of red skeletal muscle because of a developed insensitivity to insulin. We studied whether an impaired glucose clearance is present in vivo in 42-h immobilized muscles of resting rats and, furthermore, whether the exercise-induced increase in glucose clearance of red muscles is affected by prior immobilization. The 2-[3H]deoxy-D-glucose (2DG) bolus injection method was used to determine glucose clearance of individual muscles. At rest, glucose clearance was markedly impaired in rats with previously immobilized red muscles compared with nonimmobilized control rats (red gastrocnemius 0.46 +/- 0.02 vs. 0.99 +/- 0.08 and soleus 1.10 +/- 0.30 vs. 3.97 +/- 0.54 ml.min-1.100 g-1, P less than 0.005). During running (18 m/min), glucose clearance did not differ between muscles in previously immobilized and control rats. Insulin levels were always similar in the two groups and decreased during exercise. Intracellular nonphosphorylated 2DG was present in tissues with high glucose clearances. In conclusions, 42 h of immobilization markedly impairs glucose clearance of resting red muscle fibers in vivo. Apparently, physical inactivity in particular affects steps involved in insulin-mediated action that are not part of contraction-induced glucose uptake and metabolism. Presence of intracellular 2DG shows that separate determination of phosphorylated 2DG is necessary for accurate estimates of glucose metabolism and that accumulation of phosphorylated 2DG does not accurately reflect glucose transport.

RYR2 p.R169L mutation and left ventricular hypertrophy in a child with emotion-triggered sudden death

2020 ◽  
Vol 30 (7) ◽  
pp. 1039-1042
Author(s):  
Utkarsh Kohli ◽  
Lisa Kuntz ◽  
Hemal M. Nayak
Keyword(s):  
Ventricular Tachycardia ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Exercise Induced ◽  
In Vivo Effects

AbstractCatecholaminergic polymorphic ventricular tachycardia is a rare (prevalence: 1/10,000) channelopathy characterised by exercise-induced or emotion-triggered ventricular arrhythmias. There is an overall paucity of genotype-phenotype correlation studies in patients with catecholaminergic polymorphic ventricular tachycardia, and in vitro and in vivo effects of individual mutations have not been well characterised. We report an 8-year-old child who carried a mutation in the coding exon 8 of RYR2 (p.R169L) and presented with emotion-triggered sudden cardiac death. He was also found to have left ventricular hypertrophy, a combination which has not been reported before. We discuss the association between genetic variation in RYR2, particularly mutations causing replacement of arginine at position 169 of RYR2 and structural cardiac abnormalities.

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