C2 and C2C12 murine skeletal myoblast models of atrophic and hypertrophic potential: Relevance to disease and ageing?

Sharples, Adam P.; Al-Shanti, Nasser; Stewart, Claire E.

doi:10.1002/jcp.22252

Cited by 66 publications

(79 citation statements)

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“…2c). These data are consistent with observations in other in vitro models (Langen et al 2001;Sharples et al 2010;Strle et al 2004;te Pas et al 2000) and indicate that the reduced expression of these markers is responsible for the loss of differentiation capacity in C2C12BKD cells (Table 2: differentiation markers). Baker et al reported that expression of p16 Ink4a in BubR1 hypomorphic mice plays a key role in the development of age-related disorders including sarcopenia (Baker et al 2008(Baker et al , 2011.…”

Section: Bubr1 Hypomorphic C2c12 Cells Show Impaired Myogenic Differesupporting

confidence: 92%

“…Figure 2b illustrates the significant difference in fusion index between C2C12 and C2C12BKD cells from day 7 onward. In the two other in vitro models, using TNF-a-and dexamethasone-treated C2C12 cells, myotube formation was decreased in the differentiation medium but was not absent (Langen et al 2001;Sharples et al 2010;te Pas et al 2000) (Table 2: myotube formation). In contrast, in C2C12BKD cells myotube formation was essentially abolished.…”

Section: Bubr1 Hypomorphic C2c12 Cells Show Impaired Myogenic Differementioning

confidence: 96%

“…Such chronic inflammationinduced protein degradation might mediate the loss of differentiation potential in C2C12BKD cells. Indeed, addition of TNF-a prevents C2C12 myoblasts differentiation through activation of nuclear factor- kappa B (Langen et al 2001;Sharples et al 2010). However, increased expression of proinflammatory cytokines has not been reported on C2C12 models for muscle loss (Table 2: proinflammatory cytokines).…”

Section: The Ubiquitin-proteasome Pathway Is Activated In C2c12bkd Cellsmentioning

confidence: 99%

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A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

et al. 2015

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Sarcopenia is the age-related loss of skeletal muscle mass and function with adverse outcomes that include physical disability, poor quality of life, and death. The detailed molecular mechanisms remain unknown. An in vitro muscle atrophy model is needed to enable mechanistic studies. To create such a model, we employed BubR1 insufficiency which causes premature ageing in mice. Using C2C12 cells, a recognized in vitro model of the skeletal muscle cell, we obtained the BubR1 hypomorphic C2C12 (C2C12BKD) cells by using shRNA. The resulting C2C12BKD cells displayed several characteristics of the sarcopenic muscle cell. In C2C12BKD cells, formation of myotubes, assessed by analysis of fusion index, was markedly reduced as was the expression of myogenin and MyoD, two marker genes for myogenesis. Moreover, the cells showed increased expression of the muscle-specific ubiquitin ligases Atrogin-1 and MuRF-1, indicating increased protein degradation through the ubiquitin-proteasome dependent proteolytic pathway. These results suggest that C2C12BKD cells are potentially useful as a novel in vitro model of sarcopenia.

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Section: Bubr1 Hypomorphic C2c12 Cells Show Impaired Myogenic Differesupporting

confidence: 92%

Section: Bubr1 Hypomorphic C2c12 Cells Show Impaired Myogenic Differementioning

confidence: 96%

Section: The Ubiquitin-proteasome Pathway Is Activated In C2c12bkd Cellsmentioning

confidence: 99%

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A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

et al. 2015

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“…Our group has further begun to elucidate potential epigenetic modulators of myoblast survival and differentiation (Saini et al2012), where activation of Sirtuin1 (histone deacetylase) reduced myoblast death and enabled differentiation in the presence of stress from TNF-α, a cytokine that is chronically up regulated in muscle loss conditions such as sarcopenia and cachexia. We have extensively shown that TNF-α impairs myoblast fusion/differentiation and myotube hypertrophy with corresponding reductions in myoD gene expression in mouse and human muscle cells (Meadows 2000;Foulstone 2001Foulstone , 2004Al-Shanti 2008;Saini 2008;Sharples 2010). Thus, together with the above studies, this perhaps provides compelling yet preliminary data suggesting that epigenetic mechanisms such as myoD methylation could be involved in TNF-α induced reduction in differentiation and myotube atrophy in muscle cells and potentially be involved in muscle cell programming/memory.…”

Section: Introductionmentioning

confidence: 99%

“…Higher TNF-α levels are strongly correlated with muscle loss, reduced strength and therefore morbidity and earlier mortality. We have extensively shown that TNF-α impairs regenerative capacity in mouse and human muscle derived stem cells (Meadows 2000;Foulstone 2001Foulstone , 2004Al-Shanti 2008;Saini 2008;Sharples 2010). We have also recently established an epigenetically mediated mechanism (SIRT1-histone deacetylase) regulating survival of myoblasts in the presence of TNF-α (Saini 2012).…”

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confidence: 99%

Skeletal muscle cells possess a ‘memory’ of acute early life TNF-α exposure: role of epigenetic adaptation

et al. 2015

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Sufficient quantity and quality of skeletal muscle is required to maintain lifespan and healthspan into older age. The concept of skeletal muscle programming or memory has been suggested to contribute to accelerated muscle decline in the elderly in association with early life stress such as fetal malnutrition. Further, muscle cells in vitro appear to remember the in vivo environments from which they are derived (e.g. cancer, obesity, type II diabetes, physical inactivity and nutrient restriction). Tumour-necrosis factor alpha (TNF-α) is a pleiotropic cytokine that is chronically elevated in sarcopenia and cancer cachexia. Higher TNF-α levels are strongly correlated with muscle loss, reduced strength and therefore morbidity and earlier mortality. We have extensively shown that TNF-α impairs regenerative capacity in mouse and human muscle derived stem cells (Meadows 2000;Foulstone 2001Foulstone , 2004Al-Shanti 2008;Saini 2008;Sharples 2010). We have also recently established an epigenetically mediated mechanism (SIRT1-histone deacetylase) regulating survival of myoblasts in the presence of TNF-α (Saini 2012). We therefore wished to extend this work in relation to muscle memory of catabolic stimuli and the potential underlying epigenetic modulation of muscle loss. To enable this aim; C2C12 myoblasts were cultured in the absence or presence of early TNF-α (early proliferative lifespan) followed by 30 population doublings in the absence of TNF-α, prior to the induction of differentiation in low serum media (LSM) in the absence or presence of late TNF-α (late proliferative lifespan). The cells that received an early plus late lifespan dose of TNF-α exhibited reduced morphological (myotube number) and biochemical (creatine kinase activity) differentiation vs. control cells that underwent the same number of proliferative divisions but only a later life encounter with TNF-α. This suggested that muscle cells had a morphological memory of the acute early lifespan TNF-α encounter. Importantly, methylation of myoD CpG islands were increased in the early TNF-α cells, 30 population doublings later, suggesting that even after an acute encounter with TNF-α, the cells have the capability of retaining elevated methylation for at least 30 cellular divisions. Despite these fascinating findings, there were no further increases in myoD methylation or changes in its gene expression when these cells were exposed to a later TNF-α dose suggesting that this was not directly responsible for the decline in differentiation observed. In conclusion, data suggest that elevated myoD methylation is retained throughout muscle cells proliferative lifespan as result of early life TNF-α treatment and has implications for the epigenetic control of muscle loss.

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2008

Arthritis Rheum

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C₂ and C₂C₁₂ murine skeletal myoblast models of atrophic and hypertrophic potential: Relevance to disease and ageing?

Cited by 66 publications

References 59 publications

A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

Skeletal muscle cells possess a ‘memory’ of acute early life TNF-α exposure: role of epigenetic adaptation

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