Myostatin regulates pituitary development and hepatic IGF1

Area of Science:

• Endocrinology
• Muscle Physiology
• Developmental Biology

Background:

• Myostatin inhibitors are developed for muscle-wasting diseases.
• Myostatin/activin receptors are present in non-muscle tissues, raising concerns about off-target effects.
• Myostatin's role beyond muscle growth is not fully understood.

Purpose of the Study:

• To investigate myostatin's role in pituitary development and growth hormone (GH) regulation.
• To explore myostatin's impact on liver GH action.
• To assess potential off-target effects of myostatin inhibition.

Main Methods:

• Utilized a novel myostatin-null label-retaining mouse model (Jekyll mice).
• Analyzed pituitary stem, transit-amplifying, and progenitor cell pools.
• Performed experiments with recombinant myostatin on pituitary cell cultures and primary hepatocytes.
• Examined muscle fiber size in mice with combined myostatin and liver IGF1 deficiency (LID-o-Mighty mice).

Main Results:

• Jekyll mice showed accelerated depletion of pituitary stem/progenitor cells compared to wild-type.
• Jekyll pituitaries exhibited increased GH and prolactin levels, with more somatotropes and lactotropes.
• Recombinant myostatin stimulated GH release and gene expression in pituitary cells but inhibited prolactin release.
• In hepatocytes, myostatin blocked GH-stimulated IGF1 and acid-labile subunit expression while increasing IGF-binding protein-1.
• Mice lacking both myostatin and liver IGF1 had smaller muscle fibers than myostatin-null mice.

Conclusions:

• Myostatin plays a regulatory role in pituitary development and function.
• Myostatin's inhibitory effect on muscle growth may be partly mediated by attenuating liver GH action.
• Circulating myostatin inhibitors could lead to unintended consequences in the pituitary, liver, and other tissues.