Serum electrolyte concentrations and skeletal muscle excitability in vivo

Normal muscle has a resting potential of −85 mV, but in a number of situations there is depolarization of the resting potential that alters excitability. To better understand the effect of resting potential on muscle excitability we attempted to accurately simulate excitability at both normal and depolarized resting potentials. To accurately simulate excitability we found that it was necessary to include a resting potential–dependent shift in the voltage dependence of sodium channel activation and fast inactivation. We recorded sodium currents from muscle fibers in vivo and found that prolonged changes in holding potential cause shifts in the voltage dependence of both activation and fast inactivation of sodium currents. We also found that altering the amplitude of the prepulse or test pulse produced differences in the voltage dependence of activation and inactivation respectively. Since only the Nav1.4 sodium channel isoform is present in significant quantity in adult skeletal muscle, this suggests that either there are multiple states of Nav1.4 that differ in their voltage dependence of gating or there is a distribution in the voltage dependence of gating of Nav1.4. Taken together, our data suggest that changes in resting potential toward more positive potentials favor states of Nav1.4 with depolarized voltage dependence of gating and thus shift voltage dependence of the sodium current. We propose that resting potential–induced shifts in the voltage dependence of sodium channel gating are essential to properly regulate muscle excitability in vivo.

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Skeletal muscle MACF1 maintains myonuclei and mitochondria localization through microtubules to control muscle functionalities

10.1101/636464 ◽

2019 ◽

Cited By ~ 2

Author(s):

Alireza Ghasemizadeh ◽

Emilie Christin ◽

Alexandre Guiraud ◽

Nathalie Couturier ◽

Valérie Risson ◽

...

Keyword(s):

Skeletal Muscle ◽

Acetylcholine Receptors ◽

Neuromuscular Junctions ◽

Muscular Diseases ◽

Microtubule Network ◽

Adult Mice ◽

Molecular Machinery ◽

Muscle Excitability

AbstractSkeletal muscle is made from multinuclear myofiber, where myonuclei are positioned at the periphery or clustered below neuromuscular junctions (NMJs). While mispositioned myonuclei are the hallmark of numerous muscular diseases, the molecular machinery maintaining myonuclei positioning in mature muscle is still unknown. Here, we identified microtubule-associated protein MACF1 as an evolutionary conserved regulator of myonuclei positioning, in vitro and in vivo, controlling the “microtubule code” and stabilizing the microtubule dynamics during myofibers maturation, preferentially at NMJs. Specifically, MACF1 governs myonuclei motion, mitochondria positioning and structure and acetylcholine receptors (AChRs) clustering. Macf1-KO in young and adult mice decreases muscle excitability and causes evolutionary myonuclei positioning alterations in adult mice, paralleled with high mitochondria content and improved resistance to fatigue. We present MACF1 as a primary actor of the maintenance of synaptic myonuclei and AChRs clustering, peripheral myonuclei positioning and mitochondria organization through the control of microtubule network dynamics in muscle fibers.

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Modelling the skeletal muscle injury recovery using in vivo contrast-enhanced micro-CT: a proof-of-concept study in a rat model

European Radiology Experimental ◽

10.1186/s41747-020-00163-4 ◽

2020 ◽

Vol 4 (1) ◽

Cited By ~ 1

Author(s):

Bruno Paun ◽

Daniel García Leon ◽

Alex Claveria Cabello ◽

Roso Mares Pages ◽

Elena de la Calle Vargas ◽

...

Keyword(s):

Skeletal Muscle ◽

Rat Model ◽

Muscle Injury ◽

Micro Ct ◽

Skeletal Muscle Injury ◽

Monitoring Time ◽

Contrast Enhanced Ct ◽

Contrast Enhanced ◽

Injury Recovery

Abstract Background Skeletal muscle injury characterisation during healing supports trauma prognosis. Given the potential interest of computed tomography (CT) in muscle diseases and lack of in vivo CT methodology to image skeletal muscle wound healing, we tracked skeletal muscle injury recovery using in vivo micro-CT in a rat model to obtain a predictive model. Methods Skeletal muscle injury was performed in 23 rats. Twenty animals were sorted into five groups to image lesion recovery at 2, 4, 7, 10, or 14 days after injury using contrast-enhanced micro-CT. Injury volumes were quantified using a semiautomatic image processing, and these values were used to build a prediction model. The remaining 3 rats were imaged at all monitoring time points as validation. Predictions were compared with Bland-Altman analysis. Results Optimal contrast agent dose was found to be 20 mL/kg injected at 400 μL/min. Injury volumes showed a decreasing tendency from day 0 (32.3 ± 12.0mm3, mean ± standard deviation) to day 2, 4, 7, 10, and 14 after injury (19.6 ± 12.6, 11.0 ± 6.7, 8.2 ± 7.7, 5.7 ± 3.9, and 4.5 ± 4.8 mm3, respectively). Groups with single monitoring time point did not yield significant differences with the validation group lesions. Further exponential model training with single follow-up data (R2 = 0.968) to predict injury recovery in the validation cohort gave a predictions root mean squared error of 6.8 ± 5.4 mm3. Further prediction analysis yielded a bias of 2.327. Conclusion Contrast-enhanced CT allowed in vivo tracking of skeletal muscle injury recovery in rat.

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Autophagy Deficiency by Atg4B Loss Leads to Metabolomic Alterations in Mice

Metabolites ◽

10.3390/metabo11080481 ◽

2021 ◽

Vol 11 (8) ◽

pp. 481

Author(s):

Gemma G. Martínez-García ◽

Raúl F. Pérez ◽

Álvaro F. Fernández ◽

Sylvere Durand ◽

Guido Kroemer ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Mammalian Cells ◽

Tissue Homeostasis ◽

In Vivo Studies ◽

Protective Mechanism ◽

Cardiac Damage ◽

Wide Range ◽

First Time

Autophagy is an essential protective mechanism that allows mammalian cells to cope with a variety of stressors and contributes to maintaining cellular and tissue homeostasis. Due to these crucial roles and also to the fact that autophagy malfunction has been described in a wide range of pathologies, an increasing number of in vivo studies involving animal models targeting autophagy genes have been developed. In mammals, total autophagy inactivation is lethal, and constitutive knockout models lacking effectors of this route are not viable, which has hindered so far the analysis of the consequences of a systemic autophagy decline. Here, we take advantage of atg4b−/− mice, an autophagy-deficient model with only partial disruption of the process, to assess the effects of systemic reduction of autophagy on the metabolome. We describe for the first time the metabolic footprint of systemic autophagy decline, showing that impaired autophagy results in highly tissue-dependent alterations that are more accentuated in the skeletal muscle and plasma. These changes, which include changes in the levels of amino-acids, lipids, or nucleosides, sometimes resemble those that are frequently described in conditions like aging, obesity, or cardiac damage. We also discuss different hypotheses on how impaired autophagy may affect the metabolism of several tissues in mammals.

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In vitro and in vivo activation of the insulin receptor kinase in control and denervated skeletal muscle.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)84478-2 ◽

1986 ◽

Vol 261 (19) ◽

pp. 8985-8993

Author(s):

C F Burant ◽

M K Treutelaar ◽

M G Buse

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Receptor Kinase ◽

Insulin Receptor Kinase

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Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

Cells ◽

10.3390/cells10071791 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1791

Author(s):

Rosa Scala ◽

Fatima Maqoud ◽

Nicola Zizzo ◽

Giuseppe Passantino ◽

Antonietta Mele ◽

...

Keyword(s):

Skeletal Muscle ◽

Katp Channel ◽

Ex Vivo ◽

Channel Modulation ◽

Flexor Digitorum Brevis ◽

Inflammatory Edema ◽

Flexor Digitorum ◽

Channel Currents

(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K+ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2wt/AV) and homozygous SUR2[A478V] (SUR2AV/AV) CS mice. (3) Results: In SUR2wt/AV and SUR2AV/AV mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2wt/AV, dramatically so in SUR2AV/AV mice; IC50 for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10−5 M in SUR2wt/AV and 8.6 ± 0.4 × 10−6 M in WT mice and was not measurable in SUR2AV/AV. A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2AV/AV mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] “knock-in” mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2AV/AV, with atrophy and non-inflammatory edema in different skeletal muscle phenotypes.

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Exogenous parathyroid hormone attenuates ovariectomy-induced skeletal muscle weakness in vivo

Bone ◽

10.1016/j.bone.2021.116029 ◽

2021 ◽

pp. 116029

Author(s):

Taro Fujimaki ◽

Takashi Ando ◽

Takanori Hata ◽

Yoshihiro Takayama ◽

Tetsuro Ohba ◽

...

Keyword(s):

Skeletal Muscle ◽

Parathyroid Hormone ◽

Muscle Weakness ◽

Skeletal Muscle Weakness

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Identification of the MuRF1 skeletal muscle ubiquitylome through quantitative proteomics

Function ◽

10.1093/function/zqab029 ◽

2021 ◽

Author(s):

Leslie M Baehr ◽

David C Hughes ◽

Sarah A Lynch ◽

Delphi Van Haver ◽

Teresa Mendes Maia ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Potential Role ◽

Ubiquitin Proteasome System ◽

In Vivo Electroporation ◽

Adult Mice ◽

Expression Of Genes ◽

Regulation Of Metabolism ◽

Ubiquitin Proteasome

Abstract MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere, but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.

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