Abstract
Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs) do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche. PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs) include a fibroadipogenic progenitor population (FAP) that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions. We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy (DMD), the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA) muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs.
Highlights
Duchenne muscular dystrophy (DMD) is the most common X-linked recessive disease in humans, affecting 1 in 3500 males and causing premature death in the second decade of life following cardiac and pulmonary failure (Tabebordbar et al, 2013)
We demonstrated that positive interstitial cells (PICs) include the entirety of the fibroadipogenic progenitor population (FAP) and that this subpopulation expresses follistatin (FST) and insulin-like growth factor-1 (IGF-1) that account, in part, for their promyogenic activity (Pannérec et al, 2013; Formicola et al, under review and see Mozzetta et al, 2013)
A more detailed analysis revealed that both muscle groups show a decrease in PICs and satellite cell number with age, PICs/satellite cells ratio remains unchanged in aged extraocular muscles (EOMs) as compared to young EOMs (Figure 1E)
Summary
Duchenne muscular dystrophy (DMD) is the most common X-linked recessive disease in humans, affecting 1 in 3500 males and causing premature death in the second decade of life following cardiac and pulmonary failure (Tabebordbar et al, 2013). We noted a rare population of interstitial cells that expressed Pax7 in 7 week-old EOMs, completely or partially surrounded by the basal lamina (Figure 1F), whereas we did not observe any Pax7pos interstitial cell in age-matched TA (Figures 1F,G), suggesting that a subpopulation of satellite-like cells has a different anatomical location in EOMs as compared to limb muscles.
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