Myogenin and Class II HDACs Control Neurogenic Muscle Atrophy by Inducing E3 Ubiquitin Ligases

Moresi, Viviana; Williams, Andrew H; Meadows, Eric; Flynn, Jesse M.; Potthoff, Matthew J.; McAnally, John; Shelton, John M.; Backs, Johannes; Klein, William H.; Richardson, James A.; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1016/j.cell.2010.09.004

Cited by 381 publications

(473 citation statements)

References 63 publications

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“…Mice lacking the class II HDACs, HDAC4 and HDAC5, are protected from denervation‐induced muscle atrophy (Moresi et al ., 2010), and we report an increase in HDAC4 during aging in skeletal muscle. These models will provide important insight into the mechanisms of age‐related muscle loss.…”

Section: Discussionmentioning

confidence: 50%

“…Loss of muscle mass during aging has been shown by our laboratory and others to involve significant denervation of muscle fibers (Valdez et al ., 2010; Jang et al ., 2012), and HDAC4 is elevated in skeletal muscle in response to denervation (Moresi et al ., 2010). Consistent with these observations, we report for the first time an increase in HDAC4 levels in both control and butyrate‐treated old animals (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HDAC4 inhibits Dach2, a negative regulator of myogenin, a transcription factor that regulates denervation‐induced gene expression. Mice deficient in HDAC4 and HDAC5 are protected against muscle loss in a surgical model of denervation; these mice do not upregulate the muscle‐specific E3 ligases MuRF1 or atrogin‐1 in response to denervation (Moresi et al ., 2010). Furthermore, HDAC1, a class I HDAC, induces muscle atrophy in response to disuse and nutrient deprivation (Beharry et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Walsh¹,

et al. 2015

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“…For example, myogenin can activate MURF‐1 and MAFbx expression during muscle atrophy caused by denervation (Moresi et al. 2010). Moreover, recent study by Baehr et al.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

et al. 2017

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We tested whether NF‐κB pathway is indispensable for the increase in expression of E3‐ligases and unloading‐induced muscle atrophy using IKKβ inhibitor IMD‐0354. Three groups of rats were used: nontreated control (C), 3 days of unloading/hindlimb suspension with (HS+IMD) or without (HS) IMD‐0354. Levels of IκBα were higher in HS+IMD (1.16‐fold) and lower in HS (0.82‐fold) when compared with C group. IMD‐0354 treatment during unloading: had no effect on loss of muscle mass; increased mRNA levels of MuRF1 and MAFbx; increased level of pFoxO3; and had no effect on levels of Bcl‐3, p105, and p50 proteins. Our study for the first time showed that inhibiting IKK β in vivo during 3‐day unloading failed to diminish expression of ubiquitin ligases and prevent muscle atrophy.

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“…[21][22][23][24][25][62][63][64] Moreover, we are intrigued by a possible connection between repression of myogenin by p53 and muscle aging. Skeletal muscle aging is characterized by muscle atrophy and a decline in muscle function and regenerative capacity.…”

Section: Discussionmentioning

confidence: 99%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

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Myogenin and Class II HDACs Control Neurogenic Muscle Atrophy by Inducing E3 Ubiquitin Ligases

Cited by 381 publications

References 63 publications

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

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

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

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