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

Bongers, Kale S.; Fox, Daniel K.; Ebert, Scott M.; Kunkel, Steven D.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.; Adams, Christopher M.

doi:10.1152/ajpendo.00380.2013

Cited by 121 publications

(120 citation statements)

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“…We have shown previously, that mice lacking SOD1 showed significant increase in AChR alpha mRNA levels indicating the denervation process (Jang and Van Remmen, 2011). Along with AChR mRNA, we investigated the levels of Runx1 (Wang et al, 2005), MyoD (Ishido et al, 2004) and Gadd45a (Bongers et al, 2013) and found that compared with wild-type/Sham mice, G93A/Sham mice showed several fold increases in AChR alpha, Runx1, MyoD and GADD45a mRNA levels (Figure 5 A, B, C, D) as would be expected. G93A mice who experienced a mild TBI showed further increases in these denervation markers, which were significant with AChR and Runx1 mRNA levels.…”

Section: Discussionsupporting

confidence: 59%

“…We investigated, in the gastrocnemius muscle, AChR mRNA (Jang and Van Remmen, 2011), as well as the levels of other denervation markers Runx1 (Wang et al, 2005), MyoD (Ishido et al, 2004) and Gadd45a (Bongers et al, 2013). One month after TBI compared with WT sham mice, G93A sham mice showed a several fold increase in AChR alpha, Runx1, MyoD and GADD45a mRNA levels (Figure 5 A, B, C, D) indicating denervation in the gastrocnemius muscle of these mice.…”

Section: Resultsmentioning

confidence: 99%

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The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease

et al. 2015

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Traumatic brain injury (TBI) is associated with a risk for neurodegenerative disease. Some suggest a link between TBI and motor neuron disease (MND), including Amyotrophic Lateral Sclerosis (ALS). To investigate the potential mechanisms linking TBI to MND, we measured motor function and neuropathology following mild-TBI in wild-type and a transgenic model of ALS, G93A mutant mice. Mild-TBI did not alter lifespan of G93A mice or age of onset; however, rotarod performance was impaired in G93A verses wild-type mice. Grip strength was reduced only in G93A mice after mild-TBI. Increased EMG abnormalities and markers of denervation (AchR, Runx1) indicate that mild-TBI may result in peripheral effects that are exaggerated in G93A mice. Markers of inflammation (cell edema, astrogliosis and microgliosis) were detected at 24 and 72 hours in brain and spinal cord in wild-type and G93A mice. Levels of F2-isoprostanes, a marker of oxidative stress, were increased in spinal cord 24 hours post mild-TBI in wild-type mice but not affected by TBI in G93A mice. In summary, our data demonstrate that mild-TBI induces inflammation and oxidative stress and negatively impacts muscle denervation and motor performance, suggesting mild-TBI can potentiate motor neuron pathology and influence development of MND in mice.

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Section: Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease

et al. 2015

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“…The lack of eMHC expression in old muscle treated with butyrate suggests that butyrate prevents denervation or that butyrate prevents the formation of new fibers. Furthermore, butyrate prevented the age‐related increase in Gadd45a expression, a gene that mediates denervation‐induced muscle trophy that is directly regulated by HDAC4 (Bongers et al ., 2013), and central nuclei in muscle fibers, suggesting butyrate prevents degeneration of muscle fibers. Conversely, HDAC4, AChRα, and Runx1 were increased in both control and butyrate‐treated groups, while NCAM was not affected by age or diet.…”

Section: Discussionmentioning

confidence: 95%

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

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“…Subsequently, we found that increased ATF4 expression is sufficient to induce skeletal muscle fiber atrophy (18), and ATF4 is required for skeletal muscle atrophy in some but not all contexts. For example, ATF4 is required for skeletal muscle atrophy caused by fasting or aging (18,19), but it is not required for muscle atrophy caused by muscle denervation (7). To test the hypothesis that ATF4 might be required for immobilization-induced skeletal muscle atrophy, we generated and studied muscle-specific ATF4 knockout (ATF4 mKO) mice, which lack ATF4 in skeletal muscle fibers from birth but develop normally and exhibit no apparent phenotype under basal conditions (17).…”

Section: Insights Into Disuse Muscle Atrophy Using Systems Approachesmentioning

confidence: 99%

Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence

Atherton

Greenhaff

Phillips

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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

Abstract: Bongers KS, Fox DK, Ebert SM, Kunkel SD, Dyle MC, Bullard SA, Dierdorff JM, Adams CM. Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4. Am J Physiol Endocrinol Metab 305: E907-E915, 2013.

Cited by 121 publications

References 32 publications

The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease

The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence

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