Platelet-Derived Growth Factor signaling and the role of cellular crosstalk in functional muscle growth.

Increasing the understanding of the molecular and cellular players involved in the regulation of adult skeletal muscle mass is an important open issue in current muscle biology. Muscle mass is regulated through a delicate balance between protein synthesis and protein breakdown. Under conditions of muscle hypertrophy, protein synthesis exceeds protein breakdown, resulting in an increase in the size of individual muscle fibers. In the last 20 years the key intracellular signaling pathways regulating muscle mass have been elucidated, showing an important role for IGF1–Akt–mTORC1 and Myostatin–BMP signaling in the regulation of adult skeletal muscle mass [1]. Although the intracellular signaling pathways that regulate size of muscle fibers are being unraveled, the contribution of other cell types to muscle cell growth is a more debated issue. In addition to muscle fibers, various muscle-resident cell types, like satellite cells, pericytes, and Fibro/Adipogenic Progenitors (FAPs), contribute to the maintenance, growth, and regeneration of adult skeletal muscle. Satellite cells are the best described muscle-resident cell type, and, when activated, they can proliferate and fuse to the growing fiber, thereby increasing the number of myonuclei. Satellite cells are absolutely necessary for skeletal muscle to form or to regenerate new myofibers. However, their contribution to adult muscle hypertrophy is less clear [2]. The most common hypothesis has been that for muscle fibers to maintain bigger dimensions, additional nuclei need to be added to the growing fibers, thereby preventing the myonuclear domain from becoming too big. Experimentally, the role of satellite cells in muscle hypertrophy was addressed some years ago using a transgenic mouse model, in which satellite cells were ablated from adult skeletal muscle. When overloading the plantaris muscle from these mice by synergist ablation, no impairment of the hypertrophic response was observed [3]. Furthermore, transgenic activation of Akt, or inhibition of myostatin signaling leads to muscle growth without addition of new myonuclei [4,5]. Recently, however, it was shown that muscles lacking satellite cells do not undergo fiber hypertrophy, suggesting an important role for these muscle stem cells also in the growth response [6]. Although it is not straightforward to reconcile these completely opposite results, satellite cell activation is likely to have a role in proper muscle remodeling during an intense stimulus, such as synergist ablation. Indeed, when examining muscle remodeling in satellite cell-depleted muscles at later time points after synergist ablation, there was a significant increase in muscle fibrosis and an impairment of muscle function [7]. Interestingly, this requirement for satellite cells in proper long-term muscle remodeling is due to their role in preventing muscle fibrosis generated by fibrogenic cells present in skeletal muscle [8]. It was proposed that this communication occurs through exosomes released from activated satellite cells. These results suggest an important interaction between satellite cells and other muscle-resident cells in generating a proper muscle remodeling during hypertrophy. In line with this suggested role of other cells playing a role in muscle hypertrophy, a recent study published in FEBS Letters by Sugg et al. showed that treatment of mice with an inhibitor of Platelet-Derived Growth Factor Receptor (PDGFR) completely prevents overload-induced muscle hypertrophy [9]. In overloaded muscles of inhibitor-treated mice the typical activation of Akt–S6K1 signaling and increase in transcription of extracellular matrix markers was strongly reduced, supporting the hypothesis that PDGFR inhibition compromised the hypertrophic response. PDGFR alpha is predominantly expressed in muscle-resident FAPs, which are located into the interstitial space between myofibers close to vessels [10]. PDGFR beta on the other hand is mainly localized on pericytes and PW1-positive interstitial cells in skeletal muscle. The inhibitor used by Sugg et al. cannot be used to