Abstract
Myostatin is a TGFβ family member and negative regulator of muscle size. Due to the complexity of the molecular pathway between myostatin mRNA/protein and changes in transcription, it has been difficult to understand whether myostatin plays a role in resistance exercise-induced skeletal muscle hypertrophy. To circumvent this problem, we determined the expression of a unique myostatin target gene, Mighty, following resistance exercise. Mighty mRNA increased by 6 h (82.9±24.21%) and remained high out to 48 h (56.5±19.67%) after resistance exercise. Further examination of the soleus, plantaris and tibialis anterior muscles showed that the change in Mighty mRNA at 6 h correlated with the increase in muscle size associated with this protocol (R2 = 0.9996). The increase in Mighty mRNA occurred both independent of Smad2 phosphorylation and in spite of an increase in myostatin mRNA (341.8±147.14% at 3 h). The myostatin inhibitor SKI remained unchanged. However, activated Notch, another potential inhibitor of TGFβ signaling, increased immediately following resistance exercise (83±11.2%) and stayed elevated out to 6 h (78±16.6%). Electroportion of the Notch intracellular domain into the tibialis anterior resulted in an increase in Mighty mRNA (63±13.4%) that was equivalent to the canonical Notch target HES-1 (94.4±7.32%). These data suggest that acute resistance exercise decreases myostatin signaling through the activation of the TGFβ inhibitor Notch resulting in a decrease in myostatin transcriptional activity that correlates well with muscle hypertrophy.
Highlights
Myostatin, or growth and differentiation factor (GDF-8), is a member of the transforming growth factor (TGF) b superfamily of proteins
The relationship between Mighty expression and skeletal muscle hypertrophy suggests that increasing Mighty mRNA may be important in the acute hypertrophic process
There is a small but significant increase in the expression of the myostatin target gene Mighty that correlates with the increase in muscle mass following training
Summary
Growth and differentiation factor (GDF-8), is a member of the transforming growth factor (TGF) b superfamily of proteins. Myostatin association with the activin IIB receptor (ActRIIB) increases Smad2/3-mediated transcription and represses muscle growth [1]. Interfering with the myostatin pathway at any point leads to an increase in muscle size through a poorly understood mechanism. Substantial hypertrophy occurs when myostatin is decreased genetically [2], immunologically using myostatin-specific antibodies [3] and by interfering with the activation of the activin IIB receptor (ActRIIB) either with the myostatin propeptide or the circulating inhibitor follistatin [1,4,5,6]. Impairing downstream myostatin signaling by increasing SKI, a repressor of Smads, induces substantial hypertrophy [7,8]. The fact that so many constituents of this pathway can induce muscle hypertrophy suggests myostatin plays a central role in the regulation of muscle mass by resistance exercise. Due to the complexity of measuring myostatin activity, this relationship remains unclear
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