Myostatin Neutralization Results in Preservation of Muscle Mass and Strength in Preclinical Models of Tumor-Induced Muscle Wasting

Abstract

Skeletal muscle wasting occurs in a great majority of cancer patients with advanced disease and is associated with a poor prognosis and decreased survival. Myostatin functions as a negative regulator of skeletal muscle mass and has recently become a therapeutic target for reducing the loss of skeletal muscle and strength associated with clinical myopathies. We generated neutralizing antibodies to myostatin to test their potential use as therapeutic agents to attenuate the skeletal muscle wasting due to cancer. We show that our neutralizing antimyostatin antibodies significantly increase body weight, skeletal muscle mass, and strength in non-tumor-bearing mice with a concomitant increase in mean myofiber area. The administration of these neutralizing antibodies in two preclinical models of cancer-induced muscle wasting (C26 colon adenocarcinoma and PC3 prostate carcinoma) resulted in a significant attenuation of the loss of muscle mass and strength with no effect on tumor growth. We also show that the skeletal muscle mass-and strength-preserving effect of the antibodies is not affected by the coadministration of gemcitabine, a common chemotherapeutic agent, in both non-tumor-bearing mice and mice bearing C26 tumors. In addition, we show that myostatin neutralization with these antibodies results in the preservation of skeletal muscle mass following reduced caloric intake, a common comorbidity associated with advanced cancer. Our findings support the use of neutralizing antimyostatin antibodies as potential therapeutics for cancer-induced muscle wasting.

Peptide‐2 from mouse myostatin precursor protein alleviates muscle wasting in cancer‐associated cachexia

“…Furthermore, when comparing the lung metastasis 22 days after transplantation, there was no significant difference in size or number of metastases between the 2 groups (data not shown); therefore, it is unlikely that death occurred due to lung metastasis. Similar to anti‐MSTN neutralizing Abs, peptide‐2 shows a therapeutic effect on muscle atrophy 40‐42 . In the current study, peptide‐2 increased the area of thick muscle fibers and gastrocnemius muscle weight in healthy mice, in addition to counteracting muscle atrophy in LLC‐implanted mice.…”

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

“…Next, we compared the ability of AgRP neuron activation to impair insulin sensitivity during an ITT in hM3D Gq AgRP mice pretreated with a myostatin-blocking antibody (Ab) or an isotype control immunoglobulin (Smith et al, 2015). IgG treatment had no effect on AgRP neuron-mediated insulin resistance upon CNO injection in hM3D Gq AgRP mice (Figure 5D).…”

“…Twelve hours prior to the ITT, subcutaneous (s.c.) injections of 5 mg/kg BW control IgG or anti-myostatin antibody (LSN2478185) were performed as previously described (Smith et al, 2015). The selective β3-adrenergic sympathomimetic drug CL 316,243 hydrate (1 mg/kg BW) or vehicle (saline) was co-administered together with CNO 20 min prior to the ITT.…”

Bone Pain and Muscle Weakness in Cancer Patients

“…They include bone active molecules like IGF-1 and FGF-2, myostatin (also called growth differentiation factor 8 [GDF8])[109], and IL-6. [110–113] IGF-1 and FGF-2 stimulate bone formation,[114, 115] and myostatin deficiency increases bone density.…”