Fatigue at the Neuromuscular Junction

Sieck, Gary C.; Prakash, Y. S.

doi:10.1007/978-1-4899-1016-5_7

Cited by 66 publications

(23 citation statements)

References 86 publications

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“…Muscle fatigue, or the reduction of muscle force that occurs in response to repeated stimulation, is potentially caused by a variety of mechanisms affecting the central drive to MNs, neurotransmission, and the response of the muscle fiber to neurotransmission (Sieck and Prakash, 1995). A 330 ms pulse of 70 Hz stimulation, which produces a fused tetanus, elicited a specific force of 136.9 ± 12.2 mN/mm 2 ( n = 3 from three mice; Figure 4A), similar to previous reports (Fajardo et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…NTF may result from a failure of the neuronal action potential to propagate down the axon to presynaptic terminals, a reduction of the release of neurotransmitter by presynaptic terminals, an impairment of postsynaptic sensitivity to neurotransmitter, or a disruption of the propagation of the muscle action potential along the sarcolemma (Sieck and Prakash, 1995). The mechanisms of NTF have been explored in studies of high-frequency nerve stimulation (HFS), which result in synaptic depression caused by a reduction or rundown in the release of neurotransmitter (Eccles, 1943; Otsuka et al, 1962).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Striated Muscle-Specific Myosin-Blocking Drug for the Study of Neuromuscular Physiology

Heredia

Schubert

Maligireddy

et al. 2016

Front. Cell. Neurosci.

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The failure to transmit neural action potentials (APs) into muscle APs is referred to as neuromuscular transmission failure (NTF). Although synaptic dysfunction occurs in a variety of neuromuscular diseases and impaired neurotransmission contributes to muscle fatigue, direct evaluation of neurotransmission by measurement of successfully transduced muscle APs is difficult due to the subsequent movements produced by muscle. Moreover, the voltage-gated sodium channel inhibitor used to study neurotransmitter release at the adult neuromuscular junction is ineffective in embryonic tissue, making it nearly impossible to precisely measure any aspect of neurotransmission in embryonic lethal mouse mutants. In this study we utilized 3-(N-butylethanimidoyl)-4-hydroxy-2H-chromen-2-one (BHC), previously identified in a small-molecule screen of skeletal muscle myosin inhibitors, to suppress movements without affecting membrane currents. In contrast to previously characterized drugs from this screen such as N-benzyl-p-toluene sulphonamide (BTS), which inhibit skeletal muscle myosin ATPase activity but also block neurotransmission, BHC selectively blocked nerve-evoked muscle contraction without affecting neurotransmitter release. This feature allowed a detailed characterization of neurotransmission in both embryonic and adult mice. In the presence of BHC, neural APs produced by tonic stimulation of the phrenic nerve at rates up to 20 Hz were successfully transmitted into muscle APs. At higher rates of phrenic nerve stimulation, NTF was observed. NTF was intermittent and characterized by successful muscle APs following failed ones, with the percentage of successfully transmitted muscle APs diminishing over time. Nerve stimulation rates that failed to produce NTF in the presence of BHC similarly failed to produce a loss of peak muscle fiber shortening, which was examined using a novel optical method of muscle fatigue, or a loss of peak cytosolic calcium transient intensity, examined in whole populations of muscle cells expressing the genetically-encoded calcium indicator GCaMP3. Most importantly, BHC allowed for the first time a detailed analysis of synaptic transmission, calcium signaling and fatigue in embryonic mice, such as in Vamp2 mutants reported here, that die before or at birth. Together, these studies illustrate the wide utility of BHC in allowing stable measurements of neuromuscular function.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Striated Muscle-Specific Myosin-Blocking Drug for the Study of Neuromuscular Physiology

Heredia

Schubert

Maligireddy

et al. 2016

Front. Cell. Neurosci.

View full text Add to dashboard Cite

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“…This was accomplished by defining a force-metabolic fatigue function (13), which was obtained from curve-fitting of the measured force output versus the corresponding metabolic variable. Incorporating the history of Pi into our model provides a reliable prediction for the force capacity during postrest stimulation fatigue following a rest duration of 1 min.…”

Section: Discussionmentioning

confidence: 99%

“…It should be borne in mind that impairment and/ or failure of some or all of the above-mentioned processes are associated with a peripheral regulatory mechanisms which prevent the reduction of the muscle's energy reserves below their critical level [9], [11], [12]. Such regulation mechanisms incorporate susceptibility of a muscle to high frequency fatigue, which is attributed to the failure of neuromuscular transmission, action potential blocking, or low frequency fatigue which is connected to impairment of the excitation-contraction coupling mechanisms and of the rate of ATP hydrolysis [9], [11], [13]. In order to improve fatigue resistance of the muscle during FES, low-frequency stimulation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Hz) is usually used [1], [14].…”

mentioning

confidence: 99%

“…Such regulation mechanisms incorporate susceptibility of a muscle to high frequency fatigue, which is attributed to the failure of neuromuscular transmission, action potential blocking, or low frequency fatigue which is connected to impairment of the excitation-contraction coupling mechanisms and of the rate of ATP hydrolysis [9], [11], [13]. In order to improve fatigue resistance of the muscle during FES, low-frequency stimulation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Hz) is usually used [1], [14]. In this case peripheral fatigue is thought to be further away from the neuromuscular junction, thus incorporating propagation of action potentials in the muscle membrane, excitation-contraction coupling, and creation of actin-myosin crossbridges [11].…”

mentioning

confidence: 99%

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EMG and metabolite-based prediction of force in paralyzed quadriceps muscle under interrupted stimulation

Levin

Mizrahi

1999

IEEE Trans. Rehab. Eng.

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Abstract-A major issue associated with functional electrical stimulation (FES) of a paralyzed limb is the decay with time of the muscle force as a result of fatigue. A possible means to reduce fatigue during FES is by using interrupted stimulation, in which fatigue and recovery occur in sequence. In this study, we present a model which enables us to evaluate the temporal force generation capacity within the electrically activated muscle during first stimulation fatigue, i.e., when the muscle is activated from unfatigued initial conditions, and during postrest stimulation, i.e., after different given rest durations. The force history of the muscle is determined by the activation as derived from actually measured electromyogram (EMG) data, and by the metabolic fatigue function expressing the temporal changes of muscle metabolites, from existing data acquired by in vivo

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Neuromuscular propagation after fatiguing contractions of the paralyzed soleus muscle in humans

1998

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Fatigue at the Neuromuscular Junction

Cited by 66 publications

References 86 publications

A Novel Striated Muscle-Specific Myosin-Blocking Drug for the Study of Neuromuscular Physiology

A Novel Striated Muscle-Specific Myosin-Blocking Drug for the Study of Neuromuscular Physiology

EMG and metabolite-based prediction of force in paralyzed quadriceps muscle under interrupted stimulation

Neuromuscular propagation after fatiguing contractions of the paralyzed soleus muscle in humans

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