Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides

Abstract

The Cellular Communication Network (CCN) family of matricellular proteins comprises six proteins that share conserved structural features and play numerous biological roles. These proteins can interact with several receptors or soluble proteins, regulating cell signaling pathways in various tissues under physiological and pathological conditions. In the skeletal muscle of mammals, most of the six CCN family members are expressed during embryonic development or in adulthood. Their roles during the adult stage are related to the regulation of muscle mass and regeneration, maintaining vascularization, and the modulation of skeletal muscle fibrosis. This work reviews the CCNs proteins' role in skeletal muscle physiology and disease, focusing on skeletal muscle fibrosis and its regulation by Connective Tissue Growth factor (CCN2/CTGF). Furthermore, we review evidence on the modulation of fibrosis and CCN2/CTGF by the renin-angiotensin system and the kallikrein-kinin system of vasoactive peptides.

Keywords: CCN; CCN2/CTGF; KKS; cellular communication network; fibrosis; skeletal muscle; vasoactive peptides.

Figure 1

Pathological changes associated with neuromuscular diseases are concomitant with alterations in the levels of some CCNs. The healthy skeletal muscle presents myofibers of homogenous size with peripheric nuclei, accompanied by communication with motor neurons through normal neuromuscular junctions (NMJ). Muscle fibers are surrounded by regular levels of ECM, and few interstitial cells. Surrounding each fiber, capillaries assure the availability of nutrients and oxygen (inset, red dots). We classified different muscle pathologies into two groups schematized on the right. The picture on top shows significant heterogeneity in the size of myofibers and centrally located nuclei due to consecutive rounds of degeneration/regeneration. There is an increased number of interstitial cells, corresponding to cells from the immune system and myofibroblasts that contribute to the excessive accumulation of ECM proteins. Capillary density is lower, which limits oxygen availability. Generally, the NMJ is also compromised. These characteristics are present in muscular dystrophies, muscle overuse, and chronic muscle damage. At the bottom, the whole muscle and myofibers are smaller, and motor neurons and NMJ are significantly affected. There is an increment in the number of interstitial cells, significantly increased ECM accumulation, and reduced capillary density. These features are frequent in muscle atrophy due to neurodegenerative diseases, denervation, disuse, metabolic diseases, cachexia, and sarcopenia. CCNs alterations in these two groups of skeletal muscle diseases are indicated. Up and down arrows indicate up- and down regulation, respectively, at mRNA and/or protein levels (* extrapolated from cardiac muscle disease). Figure created with BioRender.com (accessed on 14 May 2021).

Figure 2

Schematic representation of the described roles for CCNs in skeletal muscle function. Each CCN connects with an arrow when it facilitates a specific process and connects with a blunt line when it inhibits a process. Dotted lines correspond to extrapolated data from cardiac muscle, which has not yet been confirmed in skeletal muscle. Figure created with BioRender.com (accessed on 14 May 2021).

Figure 3

RAS and KKS in skeletal muscle. The subsequent enzymatic cleavage (shown as scissors) of Angiotensinogen and Kininogen, leads to the release of active peptides which activate specific receptors. The Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS) of vasoactive peptides modulate CCN2/CTGF and possibly other CCNS, regulating skeletal muscle fibrosis. The activation of the canonical RAS promotes CCN2/CTGF, muscle fibrosis, and inflammation. On the other hand, alternative RAS and KKS protect skeletal muscle from damage and fibrosis. Figure created with BioRender.com (accessed on 14 May 2021).