Pleiotropic Effects of Myostatin are Associated with Differences in Stem/Progenitor Cell Pools

Melissa Jackson

Myostatin is best known as a negative regulator of skeletal muscle growth, although it influences a number of physiological and developmental systems. Moreover, the myokine circulates, and based on limited studies with young myostatin null (mstn–/ –) mice, is suspected to regulate several tissues commonly impacted by age–related disease states including sarcopenia, osteoporosis, heart failure and type 2 diabetes mellitus. We therefore determined the long–term effects of myostatin deletion on aging mstn–/ – mice (12 — 20 m.o.). Although body weights were similar in wild–type and mstn–/ – mice, lean fat–free mass and skeletal muscles were significantly heavier in mstn–/ – mice. These differences were accompanied by lower adiposity and adipocyte size. Hearts were also heavier in mstn–/ – mice and exhibited signs of dilated cardiomyopathy at rest, although mstn–/ – mice responded better to isoproterenol stress tests with greater increases in fractional shortening and ejection fraction; changes consistent with physiological cardiac hypertrophy. These data suggest that attenuating myostatin could potentially prevent or possibly treat many pathological conditions that develop with age. All of the noted differences are capable of being influenced by changes to tissue–specific stem/progenitor cells, either during development or in adult tissues. Thus, we generated doxycycline–inducible label–retaining mice with wild–type and mstn–/ – backgrounds (Jekyll mice) where stem/progenitor cells were preferentially labeled with a histone 2B/GFP fusion protein. Jekyll mice were born with fewer label–retaining cells (LRCs) in skeletal muscle and heart consistent with increased stem/progenitor cell contributions to embryonic growth of both tissues. Levels of SERCA2a, PLN and β2–adrenergic receptors were also elevated in mstn–/ – hearts and this explains the increased contractility and β2–adrenergic sensitivity of mstn–/ – cardiac muscle. Furthermore, Jekyll mice were born with more LRCs in fat despite significantly smaller tissue weights, indicating an enhanced adipoprogenitor pool. Tibia LRC counts tended to be lower in Jekyll neonates, but not adults, suggesting that previously noted enhancements in mstn–/ – bone densities are likely compensatory to increased muscle mass. These data together suggest that myostatin significantly influences the stem/progenitor cell pools of different tissues and the expression of Ca2+–handling proteins in the heart, which partly explains the pleiotropic phenotype that occurs with myostatin attenuation.

Pleiotropic Effects of Myostatin are Associated with Differences in Stem/Progenitor Cell Pools

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