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. 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.

Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice

“…A substantial increase in muscle mass, muscle fiber diameter and contractile properties through down-regulation of myostatin has been also reported in other preclinical and clinical trials 10,20–22 . In contrast, we observed the body weight, muscle mass, and muscle structure of treated mice normalized towards the wild-type properties.…”

Effects of sex steroids on bones and muscles: Similarities, parallels, and putative interactions in health and disease

“…A dissociation between muscle mass and bone mass is also implied by the dissimilar curves depicting the rate of gain and loss of bone mineral density as compared to the gain and loss of muscle mass as a function of age in humans [159]. Similarly, in aged mice receiving a myostatin inhibitor increased muscle mass and muscle fiber size is not accompanied by increased bone density or bone strength [160]. …”

Effect of the Lipoxygenase Inhibitor Baicalein on Muscles in Ovariectomized Rats

“…The endocrine axis between muscle and bone, consisting of insulin-like growth factor 1, interleukins (ILs) 6, 7, and 15, and osteoglycin, and vice versa for sclerostin with its muscle counterparts myostatin and osteocalcin, is impaired in osteoporosis and, therefore, in sarcopenia—they seem to be “two sides of the same coin” [16–19]. Recent studies also showed a significant loss of number, thickness, and capillarization of muscle fibres with a majority of type II fibre loss [20–22].…”