Force-Frequency Relationship of Human Atrial Muscle in Vitro: Beta-Adrenergic Mechanisms

1968 ◽  
Vol 76 (4) ◽  
pp. 680-692 ◽  
Author(s):  
Joseph V. Levy
Keyword(s):  
Force Frequency ◽  
Beta Adrenergic ◽  
Adrenergic Mechanisms ◽  
Atrial Muscle ◽  
Frequency Relationship ◽  
Relationship Of

Abstract 15596: Maturation of Hipsc-cm Electrophysiological and Contractile Function for Enhanced Sensitivity of Cardiac Safety Assays

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Heather B Hayes ◽  
Anthony M Nicolini ◽  
Colin Arrowood ◽  
Daniel Millard
Keyword(s):  
Contractile Function ◽  
Induced Pluripotent Stem Cell ◽  
Force Frequency ◽  
Cardiac Safety ◽  
Electrophysiological Response ◽  
Mechanical Conditioning ◽  
Enhanced Sensitivity ◽  
Frequency Relationship ◽  
Positive Force

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have significantly advanced in vitro cardiac safety and disese modeling, yet remain an immature representation of human myocytes. Electrical or mechanical conditioning of hiPSC-CMs facilitates functional maturation, as measured by a positive force-frequency relationship, but current in vitro protocols require 2-4 weeks of conditioning. Using array-based contractility and local electrical stimulation, we detected functionally mature phenotypes and compound responses in hiPSC-CMs after only 48 hours of chronic pacing. To mature cardiomyocytes, hiPSC-CMs were cultured on 24- and 96-well MEA plates with a dedicated stimulation electrodes. Later, hiPSC-CMs were electrically or optically paced at 2Hz for 48 hours. Multimodal measures quantified contractile and electrophysiological responses to varied pacing rates and compound addition. After 48 hours of pacing, hiPSC-CMs displayed shortened repolarization timing compared to before chronic pacing (baseline: 423 +/- 21 ms; matured: 316 +/- 15 ms), without significant beat period changes (baseline: 1255 +/- 40 ms; matured: 1314 +/- 84 ms). Contractile beat amplitude was measured using array-based impedance during spontaneous beating and at increasing pacing rates (1, 1.2, 1.5, 2, and 2.5 Hz). Before chronic pacing, beat amplitude decreased with increasing pacing rate; after chronic pacing, the same wells displayed increased beat amplitudes with increasing pacing rate. The matured wells also showed enhanced sensitivity to positive inotropes, such as isoproterenol, digoxin, omecamtiv mecarbil, and dobutamine. Local extracellular action potentials (LEAP) further revealed altered electrophysiological response to ranolazine, a multichannel blocker. Unpaced control wells exhibited dose-dependent APD90 prolongation in response to ranolazine, whereas matured wells showed no APD90 change. Similar results were seen with 48 hour of optogenetic pacing at 2 Hz. Overall, hiPSC-CMs chronically paced for only 48 hours exhibited more mature functional phenotypes, including a positive force-frequnecy relationship, enhanced ionotrope sensitivity, and altered compound response.

Increased susceptibility to fatigue of slow- and fast-twitch muscles from mice lacking the MG29 gene

2000 ◽  
Vol 4 (1) ◽  
pp. 43-49 ◽  
Author(s):  
RAMAKRISHNAN Y. NAGARAJ ◽  
CHRISTOPHER M. NOSEK ◽  
MARCO A. P. BROTTO ◽  
MIYUKI NISHI ◽  
HIROSHI TAKESHIMA ◽  
...  
Keyword(s):  
Major Protein ◽  
Force Frequency ◽  
Wild Type ◽  
Membrane Structures ◽  
Intracellular Ca ◽  
Slow Twitch Muscle ◽  
Fast Twitch Muscle ◽  
Frequency Relationship ◽  
Fast Twitch

Mitsugumin 29 (MG29), a major protein component of the triad junction in skeletal muscle, has been identified to play roles in the formation of precise junctional membrane structures important for efficient signal conversion in excitation-contraction (E-C) coupling. We carried out several experiments to not only study the role of MG29 in normal muscle contraction but also to determine its role in muscle fatigue. We compared the in vitro contractile properties of three muscles types, extensor digitorum longus (EDL) (fast-twitch muscle), soleus (SOL) (slow-twitch muscle), and diaphragm (DPH) (mixed-fiber muscle), isolated from mice lacking the MG29 gene and wild-type mice prior to and after fatigue. Our results indicate that the mutant EDL and SOL muscles, but not DPH, are more susceptible to fatigue than the wild-type muscles. The mutant muscles not only fatigued to a greater extent but also recovered significantly less than the wild-type muscles. Following fatigue, the mutant EDL and SOL muscles produced lower twitch forces than the wild-type muscles; in addition, fatiguing produced a downward shift in the force-frequency relationship in the mutant mice compared with the wild-type controls. Our results indicate that fatiguing affects the E-C components of the mutant EDL and SOL muscles, and the effect of fatigue in these mutant muscles could be primarily due to an alteration in the intracellular Ca homeostasis.

Force potentiation in respiratory muscles: comparison of diaphragm and sternohyoid

1993 ◽  
Vol 264 (6) ◽  
pp. R1095-R1100 ◽  
Author(s):  
E. Van Lunteren ◽  
H. Vafaie
Keyword(s):  
Respiratory Muscle ◽  
Respiratory Muscles ◽  
Upper Airway ◽  
Rapid Onset ◽  
Force Frequency ◽  
Twitch Force ◽  
Twitch Potentiation ◽  
Early Portion ◽  
Frequency Relationship

Coordinated contraction of thoracic and pharyngeal upper airway respiratory muscles optimizes ventilation, whereas pharyngeal muscle dysfunction may lead to obstructive apneas during sleep. We hypothesized that the force potentiation exhibited by the pharyngeal respiratory muscle, the sternohyoid, in keeping with its faster contractile kinetics, would be greater than that of the thoracic respiratory muscle, the diaphragm. Rat muscles were studied in vitro at 37 degrees C with three force-potentiating protocols: posttetanic twitch potentiation, staircase phenomenon (twitch potentiation), and a classic fatigue paradigm. The sternohyoid had a faster isometric contraction time, a more rightward located force-frequency relationship, and both a more rapid onset and a greater degree of fatigue than the diaphragm. During the early portion of the fatigue protocols, the increase in force was significantly greater for the sternohyoid muscle than the diaphragm (e.g., 33 vs. 3% increase at 20 Hz, P < 0.005). During repetitive twitches at 2, 3, and 5 Hz (staircase test), sternohyoid muscle force increased more than diaphragm force at the higher stimulus frequencies (e.g., by 38 vs. 23% at 5 Hz, P < 0.01). After brief tetanic stimuli, sternohyoid twitch force increased more than diaphragm twitch force (e.g., 73 vs. 14% increase after 125 Hz tetanus, P < 0.005). These data indicate that force potentiation is exhibited by both diaphragm and sternohyoid respiratory muscles, but to different extents, when activated repetitively.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Differential activation of an identified motor neuron and neuromodulation provide Aplysia's retractor muscle an additional function

2014 ◽  
Vol 112 (4) ◽  
pp. 778-791 ◽  
Author(s):  
Jeffrey M. McManus ◽  
Hui Lu ◽  
Miranda J. Cullins ◽  
Hillel J. Chiel
Keyword(s):  
Motor Neuron ◽  
Muscle Activation ◽  
Retractor Muscle ◽  
Force Frequency ◽  
Additional Function ◽  
Jaw Muscle ◽  
Protraction Phase ◽  
Frequency Relationship

To survive, animals must use the same peripheral structures to perform a variety of tasks. How does a nervous system employ one muscle to perform multiple functions? We addressed this question through work on the I3 jaw muscle of the marine mollusk Aplysia californica's feeding system. This muscle mediates retraction of Aplysia's food grasper in multiple feeding responses and is innervated by a pool of identified neurons that activate different muscle regions. One I3 motor neuron, B38, is active in the protraction phase, rather than the retraction phase, suggesting the muscle has an additional function. We used intracellular, extracellular, and muscle force recordings in several in vitro preparations as well as recordings of nerve and muscle activity from intact, behaving animals to characterize B38's activation of the muscle and its activity in different behavior types. We show that B38 specifically activates the anterior region of I3 and is specifically recruited during one behavior, swallowing. The function of this protraction-phase jaw muscle contraction is to hold food; thus the I3 muscle has an additional function beyond mediating retraction. We additionally show that B38's typical activity during in vivo swallowing is insufficient to generate force in an unmodulated muscle and that intrinsic and extrinsic modulation shift the force-frequency relationship to allow contraction. Using methods that traverse levels from individual neuron to muscle to intact animal, we show how regional muscle activation, differential motor neuron recruitment, and neuromodulation are key components in Aplysia's generation of multifunctionality.

N-acetylcysteine administration and loaded breathing

1995 ◽  
Vol 79 (1) ◽  
pp. 340-347 ◽  
Author(s):  
G. S. Supinski ◽  
D. Stofan ◽  
R. Ciufo ◽  
A. DiMarco
Keyword(s):  
Respiratory Failure ◽  
Respiratory Arrest ◽  
Diaphragm Muscle ◽  
Glutathione Metabolism ◽  
Limiting Factor ◽  
Force Frequency ◽  
Respiratory Muscle Fatigue ◽  
Loaded Breathing ◽  
Frequency Relationship

Recent work has shown that loaded breathing produces alterations in diaphragmatic glutathione metabolism. Moreover, it has been suggested that alterations in glutathione levels may be related to the development of respiratory muscle fatigue and respiratory failure during loading. The purpose of this study was to determine whether it was possible to augment diaphragmatic stores of reduced glutathione (GSH) and thereby delay the development of respiratory failure during loaded breathing by administering N-acetylcysteine (NAC), a glutathione precursor. We compared the effects of massive inspiratory loading on saline- and NAC-treated groups of decerebrate unanesthetized rats with loading continuing until respiratory arrest occurred. As controls, we also studied unloaded saline- and NAC-treated animals. After arrest, diaphragms were excised, measurement was made of diaphragmatic GSH and oxidized glutathione (GSSG) concentrations, and assessment was made of in vitro diaphragmatic contractility (i.e., the force-frequency relationship and in vitro fatigability). We found that loading of saline-treated animals produced reductions in the diaphragmatic force-frequency curve, reductions in GSH, and increases in GSSG levels. NAC administration blunted loading-induced decreases in diaphragmatic GSH levels and reduced the in vitro fatigability of excised diaphragm muscle strips. NAC did not significantly alter the time to respiratory arrest, however, and also failed to alter the effect of loaded breathing on the diaphragmatic force-frequency relationship. These findings suggest that free radical-mediated GSH depletion is not the limiting factor determining the development of respiratory failure in this model of loaded breathing.

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