Inhibiting myostatin signaling prevents femoral trabecular bone loss and microarchitecture deterioration in diet-induced obese rats

Abstract

Besides resulting in a dramatic increase in skeletal muscle mass, myostatin (MSTN) deficiency has a positive effect on bone formation. However, the issue about whether blocking MSTN can inhibit obesity-induced bone loss has not been previously investigated. In the present study, we have evaluated the effects of MSTN blocking on bone quality in high-fat (HF), diet-induced obese rats using a prepared polyclonal antibody for MSTN (MsAb). Twenty-four rats were randomly assigned to the Control, HF and HF þ MsAb groups. Rats in the HF þ MsAb group were injected once a week with purified MsAb for eight weeks. The results showed that MsAb significantly reduced body and fat weight, and increased muscle mass and strength in the HF group. MicroCT analysis demonstrated that obesity-induced bone loss and architecture deterioration were significantly mitigated by MsAb treatment, as evidenced by increased bone mineral density, bone volume over total volume, trabecular number and thickness, and decreased trabecular separation and structure model index. However, neither HF diet nor MsAb treatment had an impact on femoral biomechanical properties including maximum load, stiffness, energy absorption and elastic modulus. Moreover, MsAb significantly increased adiponectin concentrations, and decreased TNF-a and IL-6 levels in diet-induced obese rats. Taken together, blocking MSTN by MsAb improves bone quality in diet-induced obese rats through a mechanotransduction pathway from skeletal muscle, and the accompanying changes occurring in the levels of circulating adipokines and pro-inflammatory cytokines may also be involved in this process. It indicates that the administration of MSTN antagonists may be a promising therapy for treating obesity and obesity-induced bone loss.

Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss

“…3A), in line with prior reports that myostatin suppression leads to reduced serum TNFα level [41]. Bone marrow expression of GADD45, the gene for growth arrest and DNA damage repair and also a downstream target of TGFβ signaling [42], was lower in the ActRIIB.Fc-treated group as compared to the control group (Fig.…”

“…This effect was associated with reduced bone marrow expression of TNFα, GADD45 and SOST in the SIV-infected monkeys. This observation is in agreement with previous reports that these genes are mutually inducible and subject to induction during chronic inflammatory diseases and by myostatin per se [41,47,52]. Importantly, treatment with ActRIIB.Fc results in continuous bone growth without affecting serum testosterone levels, suggesting that its bone effect occurs independently or downstream of testosterone, consistent with a previous report that ActRIIB.Fc reverses bone loss induced by androgen-deprivation in rodents [28].…”

Effect of exercise on bone in poorly controlled type 1 diabetes mediated by the ActRIIB/Smad signaling pathway

“…The role of MSTN in muscle growth regulation and the disruption of its gene have been demonstrated to cause muscle hypertrophy and increase bone mass. Our previous work showed that blocking MSTN with a polyclonal anti-MSTN antibody preparation improves the trabecular bone microstructure (42), suggesting that therapeutic modulation of MSTN in vivo may be an effective strategy for preserving muscle mass and bone metabolism with diabetes. In the present study, weight-bearing running significantly inhibited STZ-induced MSTN expression, indicating that the inhibition of MSTN may alleviate STZ-induced diabetic muscle atrophy.…”

Myostatin serum concentrations are correlated with the severity of knee osteoarthritis

“…9 TNF-α stimulation enhanced the myostatin expression via the NF-κB pathway. 18 Thus, myostatin likely interacts with inflammatory cytokines and contributes to the presence and progression of OA. 16 TNF-α can activate myostatin through the NF-κB pathway in myotubes, 17 but inhibition of the NF-κB pathway can inactivate myostatin.…”

“…17 Moreover, silencing myostatin with myostatin antibody decreases TNF-α and IL-6 levels. 18 Thus, myostatin likely interacts with inflammatory cytokines and contributes to the presence and progression of OA.…”