Charge, Sophie B. P., and Michael A. Rudnicki. Cellular and Molecular Regulation of Muscle Regeneration. Physiol Rev 84: 209–238, 2004; 10.1152/physrev.00019.2003.—Under normal circumstances, mamma...

Cellular and Molecular Regulation of Muscle Regeneration

Mice and cattle with genetic deficiencies in myostatin exhibit dramatic increases in skeletal muscle mass, suggesting that myostatin normally suppresses muscle growth. Whether this increased muscling results from prenatal or postnatal lack of myostatin activity is unknown. Here we show that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss analogous to that seen in human cachexia syndromes. These data indicate that myostatin acts systemically in adult animals and may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired.

https://science.sciencemag.org/content/sci/296/5572/1486.full.pdf

Induction of cachexia in mice by systemically administered myostatin

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to be a negative regulator of myogenesis. Here we show that myostatin functions by controlling the proliferation of muscle precursor cells. When C2C12 myoblasts were incubated with myostatin, proliferation of myoblasts decreased with increasing levels of myostatin. Fluorescence-activated cell sorting analysis revealed that myostatin prevented the progression of myoblasts from the G1- to S-phase of the cell cycle. Western analysis indicated that myostatin specifically up-regulated p21Waf1, Cip1, a cyclin-dependent kinase inhibitor, and decreased the levels and activity of Cdk2 protein in myoblasts. Furthermore, we also observed that in myoblasts treated with myostatin protein, Rb was predominately present in the hypophosphorylated form. These results suggests that, in response to myostatin signaling, there is an increase in p21 expression and a decrease in Cdk2 protein and activity thus resulting in an accumulation of hypophosphorylated Rb protein. This, in turn, leads to the arrest of myoblasts in G1-phase of cell cycle. Thus, we propose that the generalized muscular hyperplasia phenotype observed in animals that lack functional myostatin could be as a result of deregulated myoblast proliferation.

Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.

Myostatin Inhibits Myoblast Differentiation by Down-regulating MyoD Expression

Myostatin is a secreted protein that acts as a negative regulator of skeletal muscle mass. During embryogenesis, myostatin is expressed by cells in the myotome and in developing skeletal muscle and acts to regulate the final number of muscle fibers that are formed. During adult life, myostatin protein is produced by skeletal muscle, circulates in the blood, and acts to limit muscle fiber growth. The existence of circulating tissue-specific growth inhibitors of this type was hypothesized over 40 years ago to explain how sizes of individual tissues are controlled. Skeletal muscle appears to be the first example of a tissue whose size is controlled by this type of regulatory mechanism, and myostatin appears to be the first example of the long-sought chalone.

Regulation of muscle mass by myostatin

Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation

Myostatin, a member of the TGF-beta superfamily, is a key negative regulator of skeletal muscle growth. The role of myostatin during skeletal muscle regeneration has not previously been reported. In the present studies, normal Sprague-Dawley and growth hormone (GH)-deficient (dw/dw) rats were administered the myotoxin, notexin, in the right M. biceps femoris on day 0. The dw/dw rats then received either saline or human-N-methionyl GH (200microg/100g body weight/day) during the ensuing regeneration. Normal and dw/dw M. biceps femoris were dissected on days 1, 2, 3, 5, 9 and 13, formalin-fixed, then immunostained for myostatin protein. Immunostaining for myostatin revealed high levels of protein within necrotic fibres and connective tissue of normal and dw/dw damaged muscles. Regenerating myotubes contained no myostatin at the time of fusion (peak fusion on day 5), and only low levels of myostatin were observed during subsequent myotube enlargement. Fibres which survived assault by notexin (survivor fibres) contained moderate to high myostatin immunostaining initially. The levels in both normal and dw/dw rat survivor fibres decreased on days 2-3, then increased on days 9-13. In dw/dw rats, there was no observed effect of GH administration on the levels of myostatin protein in damaged muscle. The low level of myostatin observed in regenerating myotubes in these studies suggests a negative regulatory role for myostatin in muscle regeneration.

Myostatin regulation during skeletal muscle regeneration.

Myostatin inhibits skeletal muscle development. Therefore, we sought to determine whether larger body and muscle mass in male mice was associated with lower mRNA and protein expression of myostatin...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00282.2002

Sexual dimorphism is associated with decreased expression of processed myostatin in males.

This study tested whether administration of insulin-like growth factor-II (IGF-II) enhances muscle regeneration. Rat biceps femoris muscle was damaged with notexin and then IGF-II was administered for up to 7 days. Results show that the proportion of nuclei containing or surrounded by immunoreactivity to MyoD, myogenin, and developmental myosin heavy chain (dMHC) is less in the IGF-II treatment group relative to the control group on days 1 (p=0.057), 2 (p=0.034), and 3 (p=0.047), respectively. This indicates a delay in muscle precursor cell (MPC) proliferation and differentiation with IGF-II administration. This effect was not associated with decreased binding capacity of the type 1 IGF receptor, as determined by receptor autoradiography in day 1 muscle sections (NS), but was associated with inhibition of phagocytic processes. The cross-sectional area of regenerating muscle fibers was significantly greater in the IGF-II treatment group than in the control group by day 7 (p=0.0092). The enhancing effect of IGF-II on late muscle regeneration, when the main process taking place is fiber enlargement, coincides with the period in which IGF-II is normally expressed by regenerating muscle, indicating that greater endogenous production of IGF-II would be associated with improved regeneration.

Sonnie P. Kirk

Papers

Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation

Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.

Myostatin regulation during skeletal muscle regeneration.

Sexual dimorphism is associated with decreased expression of processed myostatin in males.

Insulin-like growth factor-II delays early but enhances late regeneration of skeletal muscle.