A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength

Phonepasong Arounleut, Peter Bialek, Li Fang Liang, Sunil Upadhyay, Sadanand T Fulzele, Maribeth H Johnson, Mohammed Elsayed Elsalanty, Carlos M Isales, Mark W Hamrick

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20. mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+. 7%) and increased muscle fiber diameter of the extensor digitorum longus (+. 16%) and soleus (+. 6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.

Original languageEnglish (US)
Pages (from-to)898-904
Number of pages7
JournalExperimental Gerontology
Volume48
Issue number9
DOIs
StatePublished - Sep 1 2013

Fingerprint

Myostatin
Bone Density
Muscle
Bone
Bone and Bones
Muscles
Fibers
Skeletal Muscle
Body Weight
X-Ray Microtomography
Gene Knockout Techniques
Bending tests
Therapeutics
Bone Resorption
Jaw
Osteogenesis
Femur
Toughness
Assays
Sheep

Keywords

  • Anabolic therapy
  • Fractures
  • GDF-8
  • Osteoporosis
  • Sarcopenia

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

Cite this

@article{4449ca56590543a598c4aeaae1f02034,
title = "A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength",
abstract = "Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20. mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+. 7{\%}) and increased muscle fiber diameter of the extensor digitorum longus (+. 16{\%}) and soleus (+. 6{\%}) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.",
keywords = "Anabolic therapy, Fractures, GDF-8, Osteoporosis, Sarcopenia",
author = "Phonepasong Arounleut and Peter Bialek and Liang, {Li Fang} and Sunil Upadhyay and Fulzele, {Sadanand T} and Johnson, {Maribeth H} and Elsalanty, {Mohammed Elsayed} and Isales, {Carlos M} and Hamrick, {Mark W}",
year = "2013",
month = "9",
day = "1",
doi = "10.1016/j.exger.2013.06.004",
language = "English (US)",
volume = "48",
pages = "898--904",
journal = "Experimental Gerontology",
issn = "0531-5565",
publisher = "Elsevier Inc.",
number = "9",

}

TY - JOUR

T1 - A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength

AU - Arounleut, Phonepasong

AU - Bialek, Peter

AU - Liang, Li Fang

AU - Upadhyay, Sunil

AU - Fulzele, Sadanand T

AU - Johnson, Maribeth H

AU - Elsalanty, Mohammed Elsayed

AU - Isales, Carlos M

AU - Hamrick, Mark W

PY - 2013/9/1

Y1 - 2013/9/1

N2 - Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20. mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+. 7%) and increased muscle fiber diameter of the extensor digitorum longus (+. 16%) and soleus (+. 6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.

AB - Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20. mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+. 7%) and increased muscle fiber diameter of the extensor digitorum longus (+. 16%) and soleus (+. 6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.

KW - Anabolic therapy

KW - Fractures

KW - GDF-8

KW - Osteoporosis

KW - Sarcopenia

UR - http://www.scopus.com/inward/record.url?scp=84880596613&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880596613&partnerID=8YFLogxK

U2 - 10.1016/j.exger.2013.06.004

DO - 10.1016/j.exger.2013.06.004

M3 - Article

C2 - 23832079

AN - SCOPUS:84880596613

VL - 48

SP - 898

EP - 904

JO - Experimental Gerontology

JF - Experimental Gerontology

SN - 0531-5565

IS - 9

ER -