Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation

J Physiol. 2012 May 1;590(9):2151-65. doi: 10.1113/jphysiol.2011.226001. Epub 2012 Mar 5.

Abstract

Muscle fibres are multinucleated post-mitotic cells that can change dramatically in size during adulthood. It has been debated whether muscle fibre hypertrophy requires activation and fusion of muscle stem cells, the satellite cells. Myostatin (MSTN) is a negative regulator of skeletal muscle growth during development and in the adult, and MSTN inhibition is therefore a potential therapy for muscle wasting diseases, some of which are associated with a depletion of satellite cells. Conflicting results have been obtained in previous analyses of the role of MSTN on satellite cell quiescence. Here, we inhibited MSTN in adult mice with a soluble activin receptor type IIB and analysed the incorporation of new nuclei using 5-bromo-2-deoxyuridine (BrdU) labelling by isolating individual myofibres. We found that satellite cells are activated by MSTN inhibition. By varying the dose and time course for MSTN inhibition, however, we found that myofibre hypertrophy precedes the incorporation of new nuclei, and that the overall number of new nuclei is relatively low compared to the number of total myonuclei. These results reconcile some of the previous work obtained by other methods. In contrast with previous reports, we also found that Mstn null mice do not have increased satellite cell numbers during adulthood and are not resistant to sarcopaenia. Our results support a previously proposed model of hypertrophy in which hypertrophy can precede satellite cell activation. Studies of the metabolic and functional effects of postnatal MSTN inhibition are needed to determine the consequences of increasing the cytoplasm/myonuclear ratio after MSTN inhibition.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Activin Receptors, Type II / administration & dosage*
  • Age Factors
  • Aging / metabolism
  • Animals
  • Cell Proliferation / drug effects*
  • DNA Replication / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Hypertrophy
  • Injections, Intraperitoneal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Fibers, Skeletal / drug effects*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Myostatin / antagonists & inhibitors*
  • Myostatin / genetics
  • Myostatin / metabolism
  • Recombinant Fusion Proteins / administration & dosage
  • Sarcopenia / metabolism
  • Sarcopenia / pathology
  • Satellite Cells, Skeletal Muscle / drug effects*
  • Satellite Cells, Skeletal Muscle / metabolism
  • Satellite Cells, Skeletal Muscle / pathology
  • Time Factors

Substances

  • Mstn protein, mouse
  • Myostatin
  • Recombinant Fusion Proteins
  • Activin Receptors, Type II
  • activin receptor type II-B