Self-Renewal

Notch signaling is essential for myogenesis

Impaired Expression of Notch Signaling Genes in Aged Human Skeletal Muscle

Kate A. Carey, Michelle M. Farnfield, Sarah D. Tarquinio, and David Cameron-Smith

Notch signaling is essential for myogenesis and the regenerative potential of skeletal muscle;however, its regulation in human muscle is yet to be fully characterized. Increased expression of Notch3, Jagged1, Hes1, and Hes6 gene transcripts were observed during differentiation of cultured human skeletal muscle cells. Furthermore, significantly lower expressions of Notch1,
Jagged1, Numb, and Delta-like 1 were evident in muscle biopsies from older men (60–75 years old) compared to muscle from younger men (18–25 years old). Importantly, with supervised resistance exercise training, expression of Notch1 and Hes6 genes were increased and Delta-like 1 and Numb expression were decreased. The differences in Notch expression between the age groups were no longer evident following training. These results provide further evidence to support the role of Notch in the impaired regulation of muscle mass with age and suggest that some of the benefits provided by resistance training may be mediated through the Notch signaling
pathway.

The mammalian Notch receptors (Notch1, -2, -3, and -4)
are transmembrane proteins composed of an extracellular
region with multiple epidermal growth factor-like repeats
necessary for ligand binding. The Notch signaling pathway
is initiated when Notch receptor–bearing cells interact with
Notch ligands expressed on adjacent cells. Humans have at
least five Notch ligands (Jagged1 and -2, and Delta-like-1,
-3, and -4), which are themselves transmembrane proteins
with a number of epidermal growth factor-like repeats in
their extracellular domain and a unique Delta/Serrate/Lag2
(DSL)-binding domain in the amino terminus necessary for
receptor interaction. Notch–ligand interaction triggers two
proteolytic cleavages that release the Notch intracellular
domain (Notchintra) from its plasma membrane tether,
allowing it to translocate to the nucleus and bind to
a transcriptional regulator known as CBF1/Su(H)/LAG-1.
The activity of Notchintra can be inhibited by Numb through
ubiquination, which regulates the abundance and intracellular
location of the signaling molecule. The Notchintra–CBF1/
Su(H)/LAG-1 complex recruits transcriptional coactivators
that induce the gene expression of members of the Hairy-
Enhancer of Split (HES) proteins.

These proteins are basic
helix-loop-helix (bHLH) DNA binding proteins that are
thought to inhibit the expression and/or function of lineagespecifying
genes such as MyoD (involved in myogenesis)
(2). In skeletal muscle, Notch signaling contributes to
muscle development, somitogenesis, as well as the proliferation
and cell fate determination of muscle-specific
satellite cells during postnatal myogenesis (3).
Mechanical loading has been shown to augment the
proliferation and differentiation of satellite cells (4–7),
which is thought to contribute to the repair and adaptation of
the exercised muscle. Because the Notch signaling pathway
has previously been implicated in the regenerative potential
of rat muscle (1,8), we sought to examine whether components
of this pathway were transcriptionally regulated in
human skeletal muscle by exercise and during differentiation
of human myoblasts in culture. We further examined
whether the transcriptional regulation of Notch signaling
was different between young and older human skeletal
muscle both at rest and in response to a progressive 12-week
heavy resistance exercise training program. It was hypothesized
that: (i) the gene expression of members of the Notch
signaling pathway would be increased during the differentiation
of human primary cells in culture; (ii) reduced expression
of these genes would be observed in the muscle of
older compared to younger individuals; and (iii) increased
messenger RNA (mRNA) expression would be observed
following resistance training.

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Self-Renewal

Tuesday, November 13, 2007

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