scholarly journals Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

2021 ◽  
Vol 22 (6) ◽  
pp. 3252
Author(s):  
John M. Lawler ◽  
Jeffrey M. Hord ◽  
Pat Ryan ◽  
Dylan Holly ◽  
Mariana Janini Gomes ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stress Response ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Skeletal Muscle Atrophy ◽  
Positive Staining ◽  
Angiotensin Ii Receptor ◽  
Mechanical Unloading ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

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 FOXO signaling is required for disuse muscle atrophy and is directly regulated by Hsp70

2010 ◽  
Vol 298 (1) ◽  
pp. C38-C45 ◽  
Author(s):  
Sarah M. Senf ◽  
Stephen L. Dodd ◽  
Andrew R. Judge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Muscle Wasting ◽  
Dominant Negative ◽  
Disuse Muscle Atrophy ◽  
Rat Soleus Muscle ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The purpose of the current study was to determine whether heat shock protein 70 (Hsp70) directly regulates forkhead box O (FOXO) signaling in skeletal muscle. This aim stems from previous work demonstrating that Hsp70 overexpression inhibits disuse-induced FOXO transactivation and prevents muscle fiber atrophy. However, although FOXO is sufficient to cause muscle wasting, no data currently exist on the requirement of FOXO signaling in the progression of physiological muscle wasting, in vivo. In the current study we show that specific inhibition of FOXO, via expression of a dominant-negative FOXO3a, in rat soleus muscle during disuse prevented >40% of muscle fiber atrophy, demonstrating that FOXO signaling is required for disuse muscle atrophy. Subsequent experiments determined whether Hsp70 directly regulates FOXO3a signaling when independently activated in skeletal muscle, via transfection of FOXO3a. We show that Hsp70 inhibits FOXO3a-dependent transcription in a gene-specific manner. Specifically, Hsp70 inhibited FOXO3a-induced promoter activation of atrogin-1, but not MuRF1. Further studies showed that a FOXO3a DNA-binding mutant can activate MuRF1, but not atrogin-1, suggesting that FOXO3a activates these two genes through differential mechanisms. In summary, FOXO signaling is required for physiological muscle atrophy and is directly inhibited by Hsp70.

scholarly journals Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy

2015 ◽  
Vol 308 (2) ◽  
pp. E144-E158 ◽  
Author(s):  
Kale S. Bongers ◽  
Daniel K. Fox ◽  
Steven D. Kunkel ◽  
Larissa V. Stebounova ◽  
Daryl J. Murry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Skeletal Muscle Atrophy ◽  
Spermine Oxidase ◽  
Muscle Gene Expression ◽  
Fiber Size ◽  
Muscle Fiber Atrophy ◽  
Muscle Gene

Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy.

scholarly journals EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

2014 ◽  
Vol 306 (7) ◽  
pp. R470-R482 ◽  
Author(s):  
John M. Lawler ◽  
Mary Kunst ◽  
Jeff M. Hord ◽  
Yang Lee ◽  
Kumar Joshi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Muscle Fiber ◽  
Morphological Changes ◽  
Skeletal Muscle Fiber ◽  
Hindlimb Unloading ◽  
Short Term ◽  
Mechanical Unloading ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Reduced mechanical loading during bedrest, spaceflight, and casting, causes rapid morphological changes in skeletal muscle: fiber atrophy and reduction of slow-twitch fibers. An emerging signaling event in response to unloading is the translocation of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma to the cytosol. We used EUK-134, a cell-permeable mimetic of superoxide dismutase and catalase, to test the role of redox signaling in nNOSμ translocation and muscle fiber atrophy as a result of short-term (54 h) hindlimb unloading. Fischer-344 rats were divided into ambulatory control, hindlimb-unloaded (HU), and hindlimb-unloaded + EUK-134 (HU-EUK) groups. EUK-134 mitigated the unloading-induced phenotype, including muscle fiber atrophy and muscle fiber-type shift from slow to fast. nNOSμ immunolocalization at the sarcolemma of the soleus was reduced with HU, while nNOSμ protein content in the cytosol increased with unloading. Translocation of nNOS from the sarcolemma to cytosol was virtually abolished by EUK-134. EUK-134 also mitigated dephosphorylation at Thr-32 of FoxO3a during HU. Hindlimb unloading elevated oxidative stress (4-hydroxynonenal) and increased sarcolemmal localization of Nox2 subunits gp91phox (Nox2) and p47phox, effects normalized by EUK-134. Thus, our findings are consistent with the hypothesis that oxidative stress triggers nNOSμ translocation from the sarcolemma and FoxO3a dephosphorylation as an early event during mechanical unloading. Thus, redox signaling may serve as a biological switch for nNOS to initiate morphological changes in skeletal muscle fibers.

scholarly journals Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly

2007 ◽  
Vol 292 (1) ◽  
pp. E151-E157 ◽  
Author(s):  
Lex B. Verdijk ◽  
René Koopman ◽  
Gert Schaart ◽  
Kenneth Meijer ◽  
Hans H. C. M. Savelberg ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fiber ◽  
Fiber Type ◽  
The Elderly ◽  
Type I ◽  
Type Ii ◽  
Fiber Area ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy ◽  
Type Ii Fibers

Satellite cells (SC) are essential for skeletal muscle growth and repair. Because sarcopenia is associated with type II muscle fiber atrophy, we hypothesized that SC content is specifically reduced in the type II fibers in the elderly. A total of eight elderly (E; 76 ± 1 yr) and eight young (Y; 20 ± 1 yr) healthy males were selected. Muscle biopsies were collected from the vastus lateralis in both legs. ATPase staining and a pax7-antibody were used to determine fiber type-specific SC content (i.e., pax7-positive SC) on serial muscle cross sections. In contrast to the type I fibers, the proportion and mean cross-sectional area of the type II fibers were substantially reduced in E vs. Y. The number of SC per type I fiber was similar in E and Y. However, the number of SC per type II fiber was substantially lower in E vs. Y (0.044 ± 0.003 vs. 0.080 ± 0.007; P < 0.01). In addition, in the type II fibers, the number of SC relative to the total number of nuclei and the number of SC per fiber area were also significantly lower in E. This study is the first to show type II fiber atrophy in the elderly to be associated with a fiber type-specific decline in SC content. The latter is evident when SC content is expressed per fiber or per fiber area. The decline in SC content might be an important factor in the etiology of type II muscle fiber atrophy, which accompanies the loss of skeletal muscle with aging.

Effects of Emphysema on Skeletal Muscle Fiber Atrophy in Hamsters

2004 ◽  
Vol 36 (Supplement) ◽  
pp. S332
Author(s):  
John P. Mattson ◽  
Michael D. Delp ◽  
David C. Poole
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fiber ◽  
Skeletal Muscle Fiber ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The transcription factor ATF4 promotes skeletal muscle fiber atrophy during fasting

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Scott Matthew Ebert ◽  
Daniel K Fox ◽  
Kale S Bongers ◽  
Sharon E Malmberg ◽  
Christopher M Adams
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Muscle Fiber ◽  
Skeletal Muscle Fiber ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

scholarly journals Denervation does not induce muscle atrophy through oxidative stress

2017 ◽  
Vol 27 (1) ◽  
Author(s):  
Eva Pigna ◽  
Emanuela Greco ◽  
Giulio Morozzi ◽  
Silvia Grottelli ◽  
Alessio Rotini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Stress Response ◽  
Muscle Atrophy ◽  
Oxidative Stress Response ◽  
Skeletal Muscle Atrophy ◽  
Molecular Pathways ◽  
Ubiquitin Proteasome ◽  
Anti Oxidant ◽  
Kinetics Of

Denervation leads to the activation of the catabolic pathways, such as the ubiquitin-proteasome and autophagy, resulting in skeletal muscle atrophy and weakness. Furthermore, denervation induces oxidative stress in skeletal muscle, which is thought to contribute to the induction of skeletal muscle atrophy. Several muscle diseases are characterized by denervation, but the molecular pathways contributing to muscle atrophy have been only partially described. Our study delineates the kinetics of activation of oxidative stress response in skeletal muscle following denervation. Despite the denervation-dependent induction of oxidative stress in skeletal muscle, treatments with anti-oxidant drugs do not prevent the reduction of muscle mass. Our results indicate that, although oxidative stress may contribute to the activation of the response to denervation, it is not responsible by itself of oxidative damage or neurogenic muscle atrophy.

scholarly journals IκBα degradation is necessary for skeletal muscle atrophy associated with contractile claudication

2011 ◽  
Vol 300 (3) ◽  
pp. R595-R604 ◽  
Author(s):  
Brian A. Hain ◽  
Stephen L. Dodd ◽  
Andrew R. Judge
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Muscle Fiber ◽  
Hind Limb ◽  
Muscle Contractions ◽  
Limb Muscle ◽  
Flow Restriction ◽  
Hind Limb Muscle ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The arterial blockage in patients with peripheral arterial disease (PAD) restricts oxygen delivery to skeletal muscles distal to the blockage. In advanced-stage PAD patients, this creates a chronic ischemic condition in the affected muscles. However, in the majority of PAD patients, the muscles distal to the blockage only become ischemic during physical activity when the oxygen demands of these muscles are increased. Therefore, the skeletal muscle of most PAD patients undergoes repeated cycles of low-grade ischemia-reperfusion each time the patient is active and then rests. This has been speculated to contribute to the biochemical and morphological myopathies observed in PAD patients. The current study aimed to determine, using a rodent model, whether repeated hind limb muscle contractions during blood flow restriction to the hind limb muscles increases NF-κB activity. We, subsequently, determined whether an increase in NF-κB activity during this condition is required for the increased transcription of specific atrophy-related genes and muscle fiber atrophy. We found that hind limb muscle contractions during blood flow restriction to the limb increased NF-κB activity, the transcription of specific atrophy-related genes, and caused a 35% decrease in muscle fiber cross-sectional area. We further found that inhibition of NF-κB activity, via gene transfer of a dominant-negative inhibitor of κBα (d.n. IκBα), prevented the increase in atrophy gene expression and muscle fiber atrophy. These findings demonstrate that when blood flow to skeletal muscle is restricted, repeated cycles of muscle contraction can cause muscle fiber atrophy that requires NF-κB-IκBα signaling.

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