scholarly journals Skeletal muscle denervation investigations: selecting an experimental control wisely

2019 ◽  
Vol 316 (3) ◽  
pp. C456-C461 ◽  
Author(s):  
Haiming Liu ◽  
LaDora V. Thompson
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Tibial Nerve ◽  
Nerve Transection ◽  
Muscle Denervation ◽  
Crossover Effect ◽  
Proteolytic System ◽  
Experimental Control ◽  
Denervated Muscles

Unilateral denervation is widely used for studies investigating mechanisms of muscle atrophy. The “contralateral-innervated muscle” is a commonly used experimental control in denervation studies. It is not clear whether denervation unilaterally alters the proteolytic system in the contralateral-innervated muscles. Therefore, the objectives of this rapid report are 1) to determine whether unilateral denervation has an effect on the proteolytic system in contralateral-innervated control muscles and 2) to identify the changes in proteasome properties in denervated muscles after 7- and 14-day tibial nerve transection with either the contralateral-innervated muscles or intact muscles from nonsurgical mice used as the experimental control. In the contralateral-innervated muscles after 7 and 14 days of nerve transection, the proteasome activities and content are significantly increased compared with muscles from nonsurgical mice. When the nonsurgical mice are used as the experimental control, a robust increase in proteasome properties is found in the denervated muscles. This robust increase in proteasome properties is eliminated when the contralateral-innervated muscles are the experimental control. In conclusion, there is a crossover effect from unilateral denervation on proteolytic parameters. As a result, the crossover effect on contralateral-innervated muscles must be considered when an experimental control is selected in a denervation study.

Neural regulation of the enhanced uptake of glucose in skeletal muscle after endotoxin

1995 ◽  
Vol 269 (2) ◽  
pp. R437-R444 ◽  
Author(s):  
C. H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Nerve Transection ◽  
Muscle Denervation ◽  
Denervated Muscle ◽  
Muscle Type ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Sciatic Nerve Transection ◽  
Insulin Levels ◽  
Stimulation Of

Previous studies have demonstrated that in vivo injection of lipopolysaccharide (LPS) acutely stimulates glucose uptake (GU) in skeletal muscle. The purpose of the present study was to determine whether this enhanced GU is neurally mediated. In the first group of rats, a unilateral sciatic nerve transection was performed 3 h before injection of LPS, and in vivo GU was assessed using 2-[14C]deoxy-D-glucose 40 min after LPS injection. At this time, LPS-treated rats were hyperglycemic (12 mM), and insulin levels were not different from control rats. In the innervated leg, LPS increased GU 43-228%, depending on the muscle type. In contrast, LPS failed to increase GU in muscles from the denervated limb. In other experiments, somatostatin was infused to produce an insulinopenic condition before the injection of LPS. Despite insulinopenia, muscle GU was still increased by LPS. In control rats, in which the euglycemic hyperinsulinemic clamp technique was used, acute muscle denervation was shown to impair insulin-mediated GU in the presence of pharmacological, but not physiological, insulin levels. Non-insulin-mediated GU (NIMGU) was assessed in rats that were insulinopenic and hyperglycemic. In innervated muscle, NIMGU was increased 56-126 and 118-145% when the plasma glucose was elevated to 9 and 12 mM, respectively. In contrast, hyperglycemia-induced increases in NIMGU were attenuated in denervated muscle. These data demonstrate that 1) the early LPS-induced stimulation of muscle GU is mediated via a non-insulin-mediated pathway and 2) the LPS-induced increase in NIMGU in muscle is neurally mediated.

scholarly journals Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

2013 ◽  
Vol 305 (7) ◽  
pp. E907-E915 ◽  
Author(s):  
Kale S. Bongers ◽  
Daniel K. Fox ◽  
Scott M. Ebert ◽  
Steven D. Kunkel ◽  
Michael C. Dyle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Muscle Denervation ◽  
Mrna Induction ◽  
Convergence Point ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Skeletal muscle denervation causes muscle atrophy via complex molecular mechanisms that are not well understood. To better understand these mechanisms, we investigated how muscle denervation increases growth arrest and DNA damage-inducible 45α ( Gadd45a) mRNA in skeletal muscle. Previous studies established that muscle denervation strongly induces Gadd45a mRNA, which increases Gadd45a, a small myonuclear protein that is required for denervation-induced muscle fiber atrophy. However, the mechanism by which denervation increases Gadd45a mRNA remained unknown. Here, we demonstrate that histone deacetylase 4 (HDAC4) mediates induction of Gadd45a mRNA in denervated muscle. Using mouse models, we show that HDAC4 is required for induction of Gadd45a mRNA during muscle denervation. Conversely, forced expression of HDAC4 is sufficient to increase skeletal muscle Gadd45a mRNA in the absence of muscle denervation. Moreover, Gadd45a mediates several downstream effects of HDAC4, including induction of myogenin mRNA, induction of mRNAs encoding the embryonic nicotinic acetylcholine receptor, and, most importantly, skeletal muscle fiber atrophy. Because Gadd45a induction is also a key event in fasting-induced muscle atrophy, we tested whether HDAC4 might also contribute to Gadd45a induction during fasting. Interestingly, however, HDAC4 is not required for fasting-induced Gadd45a expression or muscle atrophy. Furthermore, activating transcription factor 4 (ATF4), which contributes to fasting-induced Gadd45a expression, is not required for denervation-induced Gadd45a expression or muscle atrophy. Collectively, these results identify HDAC4 as an important regulator of Gadd45a in denervation-induced muscle atrophy and elucidate Gadd45a as a convergence point for distinct upstream regulators during muscle denervation and fasting.

scholarly journals Long Non-Coding RNA Myoparr Regulates GDF5 Expression in Denervated Mouse Skeletal Muscle

2019 ◽  
Vol 5 (2) ◽  
pp. 33 ◽  
Author(s):  
Keisuke Hitachi ◽  
Masashi Nakatani ◽  
Kunihiro Tsuchida
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Myogenic Differentiation ◽  
Bmp Signaling ◽  
Skeletal Muscle Atrophy ◽  
Secretory Proteins ◽  
Non Coding Rna ◽  
Denervated Muscles ◽  
Long Non Coding Rna

Skeletal muscle is a highly plastic tissue and decreased skeletal muscle mass (muscle atrophy) results in deteriorated motor function and perturbed body homeostasis. Myogenin promoter-associated long non-coding RNA (lncRNA) Myoparr promotes skeletal muscle atrophy caused by surgical denervation; however, the precise molecular mechanism remains unclear. Here, we examined the downstream genes of Myoparr during muscle atrophy following denervation of tibialis anterior (TA) muscles in C57BL/6J mice. Myoparr knockdown affected the expression of 848 genes. Sixty-five of the genes differentially regulated by Myoparr knockdown coded secretory proteins. Among these 65 genes identified in Myoparr-depleted skeletal muscles after denervation, we focused on the increased expression of growth/differentiation factor 5 (GDF5), an inhibitor of muscle atrophy. Myoparr knockdown led to activated bone morphogenetic protein (BMP) signaling in denervated muscles, as indicated by the increased levels of phosphorylated Smad1/5/8. Our detailed evaluation of downstream genes of Myoparr also revealed that Myoparr regulated differential gene expression between myogenic differentiation and muscle atrophy. This is the first report demonstrating the in vivo role of Myoparr in regulating BMP signaling in denervated muscles. Therefore, lncRNAs that have inhibitory activity on BMP signaling may be putative therapeutic targets for skeletal muscle atrophy.

scholarly journals THE BEHAVIOR OF RESIDUAL AXONS IN PARTIALLY DENERVATED MUSCLES OF THE MONKEY

1951 ◽  
Vol 93 (3) ◽  
pp. 207-215 ◽  
Author(s):  
Mac V. Edds ◽  
Wilfred T. Small
Keyword(s):  
Sciatic Nerve ◽  
Nerve Fiber ◽  
Muscle Atrophy ◽  
Tibial Nerve ◽  
Histological Study ◽  
Nerve Fibers ◽  
Functional Improvement ◽  
Lumbosacral Plexus ◽  
Leg Muscles ◽  
Denervated Muscles

Leg muscles of the monkey have been studied following partial denervation produced by surgical elimination of from 25 to 90 per cent of the axons entering the sciatic nerve from the lumbosacral plexus. The investigation included observations on function, rate and degree of muscle atrophy, and neurohistological appearance of the affected muscles. In most of the cases, from 83 to 90 per cent of the residual nerve fibers in the peroneal and tibial nerves were destroyed and a severe paresis of the leg muscles was produced. No functional improvement was noted up to 160 days after operation, and the affected muscles became markedly atrophic. Histological examination of these muscles failed to reveal more than sporadic collateral regeneration of the residual axons. In two cases 50 and 75 per cent of the peroneal and tibial nerve fibers remained intact 63 and 200 days, respectively, after operation. The legs operated upon in these cases functioned almost normally and all muscles weighed within 11 per cent of those of the contralateral, normal leg. Histological study and counts of end-plate: nerve fiber ratios showed that many residual axons had regenerated collateral branches which entered denervated end-plates. Collateral regeneration was incomplete, however, and many end-plates remained without innervation. These results indicate that residual axons in paretic muscles of a primate do not regenerate collaterally as readily as do those of other previously studied mammals.

scholarly journals Longitudinal RNA-Seq analysis of acute and chronic neurogenic skeletal muscle atrophy

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Jeffrey T. Ehmsen ◽  
Riki Kawaguchi ◽  
Ruifa Mi ◽  
Giovanni Coppola ◽  
Ahmet Höke
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Tibial Nerve ◽  
Skeletal Muscle Atrophy ◽  
Rna Seq ◽  
Rapid Loss ◽  
Molecular Phenotype ◽  
Longitudinal Course ◽  
Acute Responses ◽  
Identify Gene Expression

Abstract Skeletal muscle is a highly adaptable tissue capable of changes in size, contractility, and metabolism according to functional demands. Atrophy is a decline in mass and strength caused by pathologic loss of myofibrillar proteins, and can result from disuse, aging, or denervation caused by injury or peripheral nerve disorders. We provide a high-quality longitudinal RNA-Seq dataset of skeletal muscle from a cohort of adult C57BL/6J male mice subjected to tibial nerve denervation for 0 (baseline), 1, 3, 7, 14, 30, or 90 days. Using an unbiased genomics approach to identify gene expression changes across the entire longitudinal course of muscle atrophy affords the opportunity to (1) establish acute responses to denervation, (2) detect pathways that mediate rapid loss of muscle mass within the first week after denervation, and (3) capture the molecular phenotype of chronically atrophied muscle at a stage when it is largely resistant to recovery.

scholarly journals Dicer-mediated miRNA processing is not involved in controlling muscle mass during muscle atrophy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Satoshi Oikawa ◽  
Jaehoon Shin ◽  
Takao Akama ◽  
Takayuki Akimoto
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Networks ◽  
Adult Skeletal Muscle ◽  
Functional Roles ◽  
Denervated Muscles ◽  
Protein Synthesis And Degradation ◽  
Synthesis And Degradation

AbstractMuscle atrophy occurs in a variety of physiological and pathological conditions. Specific molecular networks that govern protein synthesis and degradation play important roles in controlling muscle mass under diverse catabolic states. MicroRNAs (miRNAs) were previously found to be regulators of protein synthesis and degradation, and their expressions in skeletal muscle were altered in muscle wasting conditions. However, functional roles of miRNAs in muscle atrophy are poorly understood. In this study, we generated tamoxifen-inducible Dicer knockout (iDicer KO) mice and subjected them to 2 weeks of single hindlimb denervation. The expression of Dicer mRNA was significantly reduced in muscle of the iDicer KO mice compared to that of WT mice. The loss of Dicer moderately reduced levels of muscle-enriched miRNAs, miR-1, miR-133a and miR-206 in both innervated and denervated muscles of the iDicer KO mice. We also found that the extent of denervation-induced muscle atrophy as well as changes of signaling molecules related to protein synthesis/degradation pathways in the iDicer KO mice were comparable to these in WT mice. Taken together, Dicer knockout in adult skeletal muscle did not affect denervation-induced muscle atrophy.

Absence of caspase-3 protects against denervation-induced skeletal muscle atrophy

2009 ◽  
Vol 107 (1) ◽  
pp. 224-234 ◽  
Author(s):  
Pamela J. Plant ◽  
James R. Bain ◽  
Judy E. Correa ◽  
Minna Woo ◽  
Jane Batt
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Knockout Mice ◽  
Caspase 3 ◽  
Skeletal Muscle Atrophy ◽  
Wild Type ◽  
Denervated Muscle ◽  
Apoptotic Signaling ◽  
Ubiquitin Proteasome ◽  
Denervated Muscles

The ubiquitin-proteasome system is a key proteolytic pathway activated during skeletal muscle atrophy. The proteasome, however, cannot degrade intact myofibrils or actinomyosin complexes. In rodent models of diabetes mellitus and uremia, caspase-3 is involved in actinomyosin cleavage, generating fragments that subsequently undergo ubiquitin-proteasome-mediated degradation. Here, we demonstrate that caspase-3 also mediates denervation-induced muscle atrophy. At 2 wk after tibial nerve transection, the denervated gastrocnemius of caspase-3-knockout mice weighed more and demonstrated larger fiber-type-specific cross-sectional area than the denervated gastrocnemius of wild-type mice. However, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude or pattern of actinomyosin degradation, as determined by Western blotting for actin and the 14-kDa actin fragment. Similarly, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude of increase in proteasome activity, total protein ubiquitination, or atrogin-1 and muscle-specific ring finger protein 1 transcript levels. In contrast, there was an increase in TdT-mediated dUTP nick end label-positive nuclei in the denervated muscle of wild-type compared with caspase-3-knockout mice. Apoptotic signaling upstream of caspase-3 remained intact, with equivalent mitochondrial Bax translocation and cytochrome c release and caspase-9 activation in the denervated gastrocnemius muscle of wild-type and caspase-3-knockout mice. In contrast, diminished poly(ADP-ribose) polymerase cleavage in the denervated muscle of caspase-3-knockout compared with wild-type mice revealed that apoptotic signaling downstream of caspase-3 was impaired, suggesting that the absence of caspase-3 protects against denervation-induced muscle atrophy by suppressing apoptosis as opposed to ubiquitin-proteasome-mediated protein degradation.

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