Key result
Myostatin knockout in mice altered the expression of genes and proteins related to muscle energy metabolism and cell survival, revealing PI3K and apoptotic pathways as myostatin targets.
p-value: p=<0.05
Myostatin knockout in mice alters gene and protein expression in skeletal muscle, up-regulating PI3K and anti-apoptotic pathways and promoting a glycolytic metabolic shift.
Hypothesis-generating for myostatin modulation in muscle metabolism; leaves open human translation and clinical relevance.
BACKGROUND: Myostatin (MSTN), a member of the TGF-beta superfamily, has been identified as a negative regulator of skeletal muscle mass. Inactivating mutations in the MSTN gene are responsible for the development of a hypermuscular phenotype. In this study, we performed transcriptomic and proteomic analyses to detect altered expression/abundance of genes and proteins. These differentially expressed genes and proteins may represent new molecular targets of MSTN and could be involved in the regulation of skeletal muscle mass. RESULTS: Transcriptomic analysis of the Quadriceps muscles of 5-week-old MSTN-null mice (n = 4) and their controls (n = 4) was carried out using microarray (human and murine oligonucleotide sequences) of 6,473 genes expressed in muscle. Proteomic profiles were analysed using two-dimensional gel electrophoresis coupled with mass spectrometry. Comparison of the transcriptomic profiles revealed 192 up- and 245 down- regulated genes. Genes involved in the PI3K pathway, insulin/IGF pathway, carbohydrate metabolism and apoptosis regulation were up-regulated. Genes belonging to canonical Wnt, calcium signalling pathways and cytokine-receptor cytokine interaction were down-regulated. Comparison of the protein profiles revealed 20 up- and 18 down-regulated proteins spots. Knockout of the MSTN gene was associated with up-regulation of proteins involved in glycolytic shift of the muscles and down-regulation of proteins involved in oxidative energy metabolism. In addition, an increased abundance of survival/anti-apoptotic factors were observed. CONCLUSION: All together, these results showed a differential expression of genes and proteins related to the muscle energy metabolism and cell survival/anti-apoptotic pathway (e.g. DJ-1, PINK1, 14-3-3epsilon protein, TCTP/GSK-3beta). They revealed the PI3K and apoptotic pathways as MSTN targets and are in favour of a role of MSTN as a modulator of cell survival in vivo.
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Chelh et al. (2009) studied Myostatin null (hypermuscular phenotype) (n=8). Myostatin gene knockout vs. Wild-type control littermates was evaluated on Differentially expressed genes and proteins in Quadriceps muscle (p=<0.05). Myostatin knockout in mice altered the expression of genes and proteins related to muscle energy metabolism and cell survival, revealing PI3K and apoptotic pathways as myostatin targets.
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