Myostatin signals through Pax7 to regulate satellite cell self-renewal

McFarlane, Craig; Hennebry, Alex; Thomas, Mark; Plummer, Erin; Ling, Nicholas; Sharma, Mridula; Kambadur, Ravi

doi:10.1016/j.yexcr.2007.09.012

Cited by 130 publications

(125 citation statements)

References 51 publications

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“…In this study, higher myostatin level was shown to be, in part, responsible for the muscle atrophy in Smad3-null mice. This further suggests that myostatin could signal independently of Smad3 via either Smad2 or other signaling pathways, such as p38 mitogen-activated protein kinase (MAPK), c-Jun Nterminal kinase (JNK), and phosphatidylinositol 3-kinase (PI3K) pathways as shown previously [9,[39][40][41][42]. In the present manuscript, we have provided evidence to support the critical role of Smad3 in regulation of postnatal myogenesis and SC function in mice.…”

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Insupporting

confidence: 77%

“…However, other signaling pathways including Smad2 are also shown to be involved in myostatin signaling [9,13,[39][40][41][42]. In this study, higher myostatin level was shown to be, in part, responsible for the muscle atrophy in Smad3-null mice.…”

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Inmentioning

confidence: 53%

“…In contrast, increased levels of myostatin have been shown to inhibit myoblast proliferation, arresting cells at the G 1 to S transition, further resulting in reduced differentiation [7]. Furthermore, increased myostatin levels have also been shown to inhibit SC activation and self-renewal [8,9], and also result in the development of severe cachectic-like muscle wasting, through activating components of the ubiquitinproteasome pathway [37]. The data presented in this manuscript, as well as previously published reports, strongly support the notion that the increased expression of myostatin observed in Smad3-null mice may be primarily responsible for the impaired SC function and increased protein catabolism.…”

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Inmentioning

confidence: 99%

“…Moreover, systemic overexpression of myostatin in adult mice leads to the development of cachectic-like muscle wasting [6]. Myostatin functions by inhibiting myoblast proliferation and differentiation [7], as well as negatively regulating SC activation and SC self-renewal [8,9]. In addition to myostatin, TGF-β has also been shown to inhibit myogenesis [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3-null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype.

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Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Insupporting

confidence: 77%

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Inmentioning

confidence: 53%

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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“…Such a process might also explain why muscle mass was not changed even though the (mRNA) expression of the ubiquitin ligase MuRF-1 was elevated (similar as in aging human vastus lateralis muscle [36]). A possible increase in the protein degradation rate consequent to the increased MuRF-1 expression [19,37] may be attenuated by the reduced expression of myostatin in the old rats, as myostatin enhances protein degradation and reduces protein synthesis [38,39]. Alternatively, the elevated MuRF-1 occurs primarily in the denervated fibres while the decrease in myostatin occurs primarily in the fibres undergoing compensatory hypertrophy.…”

Section: Effects Of Ageingmentioning

confidence: 99%

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

et al. 2011

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Supra-physiological levels of vitamin D induce skeletal muscle atrophy, which may be particularly detrimental in already sarcopaenic elderly. Neither the cause nor whether the atrophy is fibre type specific are known. To obtain supraphysiological levels of circulating vitamin D (1,25(OH) 2 D 3 ) 27.5-month-old female Fischer 344 9 Brown Norway F1 rats were orally treated for 6 weeks with vehicle or the vitamin D analogue alfacalcidol. Alfacalcidol treatment induced a 22% decrease in body mass and 17% muscle atrophy. Fibre atrophy was restricted to type IIb fibres in the low-oxidative part of the gastrocnemius medialis only (-22%; P \ 0.05). There was a concomitant 1.6-fold increase in mRNA expression of the ubiquitin ligase MuRF-1 (P \ 0.001), whereas those of insulin-like growth factor 1 and myostatin were not affected. Circulating IL-6 was unaltered, but leptin and adiponectin were decreased (-39%) and increased (64%), respectively. The treated rats also exhibited a reduced food intake. In conclusion, supraphysiological levels of circulating 1,25(OH) 2 D 3 cause preferential atrophy of type IIb fibres, which is associated with an increased expression of MuRF-1 without evidence of systemic inflammation. The atrophy and loss of body mass in the presence of supra-physiological levels of vitamin D are primarily due to a reduced food intake.

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In vitro silencing of myostatin gene by shRNAs in chicken embryonic myoblast cells

Tripathi

Aparnathi

Patel

et al. 2013

Biotechnology Progress

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RNA interference represents one of the potential mechanisms of regulation of gene expression. Selective downregulation of myostatin (MSTN), a member of transforming growth factor-β (TGF-β) superfamily and a negative regulator of myogenesis, has been demonstrated to enhance skeletal muscle growth. In this study, we studied short hairpin RNA (shRNA)-induced myostatin gene silencing in chicken embryonic myoblast cells using seven different shRNA-expressing constructs by reverse transcription-quantitative real time PCR (RT-qPCR). Myostatin-silencing efficiency of all shRNA constructs were first evaluated in human embryonic kidney cell line 293T (HEK293T) cells, where we observed 30-75.6% reduction in myostatin expression, followed by chicken embryo myoblast cells that revealed up to 55% reduction in myostatin expression along with upregulation of MyoD by 4.65-folds. Consistent with the earlier observations, the transfection of cells with plasmids led to significant increase in interferon responsive genes OAS1 and IFN β (2-112-folds), independent of myostatin silencing in both HEK293T and chicken embryonic myoblast cells. Our study suggests that apart from shRNA sequences, cell type-specific factors may play a significant role in determining the knockdown efficiency of shRNAs.

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Myostatin signals through Pax7 to regulate satellite cell self-renewal

Cited by 130 publications

References 51 publications

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

In vitro silencing of myostatin gene by shRNAs in chicken embryonic myoblast cells

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