Linking skeletal muscle aging with osteoporosis by lamin A/C deficiency

PLoS Biol. 2020 Jun 1;18(6):e3000731. doi: 10.1371/journal.pbio.3000731. eCollection 2020 Jun.

Abstract

The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging-like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C-deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C-deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C-KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-β-gal), p16Ink4a, and p53 in lamin A/C-deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / pathology*
  • Animals
  • Antibodies, Blocking / pharmacology
  • Biomechanical Phenomena
  • Bone Resorption / complications
  • Bone Resorption / pathology
  • Cancellous Bone / drug effects
  • Cancellous Bone / pathology
  • Cell Differentiation / drug effects
  • Cellular Senescence / drug effects
  • Interleukin-6 / metabolism
  • Lamin Type A / deficiency*
  • Mice, Knockout
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology*
  • Organ Size / drug effects
  • Osteoclasts / drug effects
  • Osteoclasts / pathology
  • Osteogenesis / drug effects
  • Osteoporosis / blood
  • Osteoporosis / pathology*
  • Phenotype

Substances

  • Antibodies, Blocking
  • Interleukin-6
  • Lamin Type A