Abstract
Degenerative myopathies typically display a decline in satellite cells coupled with a replacement of muscle fibers by fat and fibrosis. During this pathological remodeling, satellite cells are present at lower numbers and do not display a proper regenerative function. Whether a decline in satellite cells directly contributes to disease progression or is a secondary result is unknown. In order to dissect these processes, we used a genetic model to reduce the satellite cell population by ~70–80% which leads to a nearly complete loss of regenerative potential. We observe that while no overt tissue damage is observed following satellite cell depletion, muscle fibers atrophy accompanied by changes in the stem cell niche cellular composition. Treatment of these mice with an Activin receptor type-2B (AcvR2B) pathway blocker reverses muscle fiber atrophy as expected, but also restores regenerative potential of the remaining satellite cells. These findings demonstrate that in addition to controlling fiber size, the AcvR2B pathway acts to regulate the muscle stem cell niche providing a more favorable environment for muscle regeneration.
Highlights
Chronic degenerative muscle diseases eventually lead to a collapse in the ability of muscle to regenerate
We observed that diphtheria toxin (DT)-induced satellite cell depletion resulted in a marked reduction (20%) in fiber size indicating that satellite cells are required to maintain proper fiber size in resting muscle (Figures 1C,D)
It has been shown previously that a soluble form of the Activin receptor type-2B (AcvR2B) (RAP031) containing the ligand-binding site inhibits AcvR2B signaling by functioning as a decoy receptor in vivo and that this inhibition results in marked hypertrophy due to inhibition of MST and activin activity (Akpan et al, 2009; Koncarevic et al, 2010; George Carlson et al, 2011; Pistilli et al, 2011)
Summary
Chronic degenerative muscle diseases eventually lead to a collapse in the ability of muscle to regenerate. During the early phase of DMD, muscle undergoes continuous rounds of degeneration/regeneration but eventually regenerative competence declines accompanied by a decrease in satellite cell number (Wallace and McNally, 2009; Mann et al, 2011; Tabebordbar et al, 2013). Whether the decline in satellite cells contributes to disease progression is unclear, in part since dissecting the relative contribution of a decreased satellite cell number in mouse DMD models is hampered by the fact that these models do not reflect the severity of disease progression in boys (Hoffman et al, 1987; Coulton et al, 1988; Tabebordbar et al, 2013)
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