The Myogenic Factor Myf5 Supports Efficient Skeletal Muscle Regeneration by Enabling Transient Myoblast Amplification

Abstract

The myogenic factor Myf5 defines the onset of myogenesis in mammals during development. Mice lacking both Myf5 and MyoD fail to form myoblasts and are characterized by a complete absence of skeletal muscle at birth. To investigate the function of Myf5 in adult skeletal muscle, we generated Myf5 and mdx compound mutants, which are characterized by constant regeneration. Double mutant mice show an increase of dystrophic changes in the musculature, although these mice were viable and the degree of myopathy was modest. Myf5 mutant muscles show a small decrease in the number of muscle satellite cells, which was within the range of physiological variations. We also observed a significant delay in the regeneration of Myf5 deficient skeletal muscles after injury. Interestingly, Myf5 deficient skeletal muscles were able to even out this flaw during the course of regeneration, generating intact muscles 4 weeks after injury. Although we did not detect a striking reduction of MyoD positive activated myoblasts or of Myf5-LacZ positive cells in regenerating muscles, a clear decrease in the proliferation rate of satellite cell-derived myoblasts was apparent in satellite cell-derived cultures. The reduction of the proliferation rate of Myf5 mutant myoblasts was also reflected by a delayed transition from proliferation to differentiation, resulting in a reduced number of myotube nuclei after 6 and 7 days of culture. We reason that Myf5 supports efficient skeletal muscle regeneration by enabling transient myoblast amplification. STEM CELLS

A WNT/β-Catenin Signaling Activator, R-spondin, Plays Positive Regulatory Roles during Skeletal Myogenesis

“…In contrast, MyoD is continuously expressed in differentiated cells (41). Adult Myf5 null mice showed severely defective muscle regeneration, implicating a Myf5 role in satellite cell function during muscle regeneration (42,43). A specific activation of MYF5 in satellite cells and C2C12 myoblasts by RSPOs strongly suggests a critical role of RSPO signaling, possibly through the ␤-catenin pathway, in regulating satellite cells at the stage of activation and myogenic commitment during muscle regeneration.…”

Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis

“…Myf5 is a myogenic regulatory factor with important roles in muscle specification and regeneration (Rudnicki et al, 1993;Cooper et al, 1999;Ustanina et al, 2007). It is highly expressed in activated satellite cells and is upregulated in zebrafish, human and murine ERMS (Cornelison and Wold, 1997;Langenau et al, 2007;Zibat et al, 2010;Rubin et al, 2011).…”

Different autonomous myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse embryogenesis

“…Immunofluorescence, in situ hybridization, lacZ staining and skeletal analysis For immunofluorescence and histological staining, cryosections were prepared and processed applying standard procedures (Schulze et al, 2005;Ustanina et al, 2007). The following antibodies were used: MF20 (DSHB), anti-myogenin (DSHB), anti-Myf5 (Santa Cruz), anti-Myod1 (clone 5.8A, Dako GbmH) and anti-Pax7 (DSHB).…”

“…Isolation of RNA was carried out using established procedures that have been described previously (Schulze et al, 2005;Ustanina et al, 2007). RT-PCR analysis was essentially done as described (Schulze et al, 2005).…”