Perlecan deficiency causes muscle hypertrophy, a decrease in myostatin expression, and changes in muscle fiber composition

Abstract

Perlecan is a component of the basement membrane that surrounds skeletal muscle. The aim of the present study is to identify the role of perlecan in skeletal muscle hypertrophy and myostatin signaling, with and without mechanical stress, using a mouse model (Hspg2 −/− -Tg) deficient in skeletal muscle perlecan. We found that myosin heavy chain (MHC) type IIb fibers in the tibialis anterior (TA) muscle of Hspg2 −/− -Tg mice had a significantly increased fiber cross-sectional area (CSA) compared to control (WT-Tg) mice. Hspg2 −/− -Tg mice also had an increased number of type IIx fibers in the TA muscle. Myostatin and its type I receptor (ALK4) expression was substantially decreased in the Hspg2 −/− -Tg TA muscle. Myostatin-induced Smad activation was also reduced in a culture of myotubes from the Hspg2 −/− -Tg muscle, suggesting that myostatin expression and its signaling were decreased in the Hspg2 −/− -Tg muscle. To examine the effects of mechanical overload or unload on fast and slow muscles in Hspg2 −/− -Tg mice, we performed tenotomy of the plantaris (fast) muscle and the soleus (slow) muscle. Mechanical overload on the plantaris muscle of Hspg2 −/− -Tg mice significantly increased wet weights compared to those of control mice, and unloaded plantaris muscles of Hspg2 −/− -Tg mice caused less decrease in wet weights compared to those of control mice. The decrease in myostatin expression was significantly profound in the overloaded plantaris muscle of Hspg2 −/− -Tg mice, compared with that of control mice. In contrast, overloading the soleus muscle caused no changes in either type of muscle. These results suggest that perlecan is critical for maintaining fast muscle mass and fiber composition, and for regulating myostatin signaling.

Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands

“…More recently, the myostatin prodomain was shown to interact with the heparin sulphate proteoglycan perlecan (Figure 2; Sengle et al 2011), which, itself, binds to fibrillin within the ECM ). An important functional consequence of this interaction is suggested from perlecan-deficient mice, which display skeletal muscle hypertrophy and reduced myostatin expression (Xu et al 2010). Finally, the prodomain of myostatin also serves as a docking site for members of the BMP-1/tolloid (BMP-1/TLD) family of extracellular metalloproteases, which activate latent myostatin in vivo (described below; Wolfman et al 2003).…”

Urinary diagnostic proteomic markers for dynapenia in cancer patients

“…Deficiencies in this molecule have been shown to cause hypertrophy. It also appears to be important in maintaining fast muscle mass, fiber composition and in regulating myostatin signaling (38). The observed upregulation of a fragment of this molecule is likely due to atrophy and might be directly linked to dynapenia.…”

Engineered matrices for skeletal muscle satellite cell engraftment and function

“…While it remains to be determined whether proteoglycans directly regulate MuSC function, proteoglycans certainly modulate the MuSC niche in an indirect manner. For instance, perlecan-deficient mice exhibit muscle hypertrophy in a myostatin-dependent manner, suggesting that perlecan is crucial for maintaining muscle mass [85]. Furthermore, proteoglycans sequester important soluble growth factors to mediate MuSC function [62,63], such as insulin-like growth factor-1 (IGF-1), hepatocyte growth factor-1 (HGF-1), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF- β), and platelet-derived growth factor (PDGF-1).…”