E-Newsletter No. 41

Genetics is a powerful tool to modify growth rate and body composition. Genetic selection has been shown to modify metabolism and its regulation. For example, an individual with a lean body is less responsive to insulin action than an individual with a fat body. Individuals with a high growth rate show higher circulating levels of insulin like growth factor-I (IGF-I) and higher hepatic IGF-I mRNA levels when compared to those with a low growth rate. Overexpression of the IGF-I gene can induce a general hyperplasia of muscle if circulating levels are increased, because IGF-I is a general enhancer of lean tissue growth. On the other hand, if overexpression is restricted to the muscle without marked modifications of circulating levels, simply muscle hypertrophy will occur.

By contrast, the myostatin (MSTN) gene, a member of the transforming growth factor-ß family, is expressed specifically in the muscle tissue and acts as a negative regulator of muscle development. Mice and cattle carrying a targeted disruption of the MSTN gene show a dramatic increase in muscle mass, which results from a combination of muscle fiber hyperplasia and hypertrophy. (See Newsletter # 4, Big Blue Double-Muscle Syndrome.) An over expression of the IGF-1 gene in the muscle tissue, or a targeted invalidation of the MSTN gene have been shown to increase muscle development in transgenic mice, which motivated us to concentrate on these two candidate genes.

Click here to learn more about myostatin

The present study was conducted to test the hypothesis that the balance of IGF-I and MSTN could contribute to restoring lost muscle mass in aged individuals with Sarcopenia (muscle loss) of aging. In addition, Myoplex® , a proprietary monoclonal antibody developed by the Lee-Benner Institute, was utilized in this preliminary study to artificially induce disruption of gene expression of the MSTN gene. The pharmacokinetics and morphological effects of Myoplex® are hereby described at the cellular level.

Myoplex^® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human MSTN protein receptor linked to the Fc portion of human IgG1. It is produced by recombinant DNA technology in a Chinese hamster ovary. It consists of 934 amino acids, and has an apparent molecular weight of approximately 150 kilodaltons.

Myoplex^® was found to bind specifically to the MSTN protein and block its interaction with cell surface MSTN protein receptors, rendering the MSTN protein inactive. A single intramuscular injection of Myoplex^® 25mg to 25 patients with Sarcopenia of aging resulted in a mean half-life of the monoclonal antibody of 7 to 10 days. After six months of twice monthly injections, patients exhibited a 2 to 7 fold increase in peak serum concentrations of their endogenous (total, free and percent free) testosterone levels. There was an approximate four-fold increase in AUC (Area Under the Curve)- range 1-7 fold- with repeated dosing.

Muscle biopsies of the Pectoralis major (PM) muscle and the Sartorious (SART) muscle were taken at baseline, two months and six months. Muscle yields from 2 and 6 months revealed a progressive muscle fiber hyperplasia and hypertrophy over baseline, more so in the PM than in the SART muscles. IGF-I and MSTN mRNA levels were monitored along with cross-sectional area of muscle fibers. Between 2 and 6 months, IGF-I mRNA levels were significantly higher than at baseline, and MSTN mRNA levels decreased during the same period. This increase in the IGF-I/MSTN ratio suggested that it could be contributing to the explosive growth observed during that period. Our results support the hypothesis that the relative levels of IGF-I and MSTN mRNA may participate to set muscle growth rate, and that the novel monoclonal antibody Myoplex^® could be an effective regulatory intervention in the clinical management of Sarcopenia of aging.

For more information on sarcopenia see:
E-Newsletter No. 4 Big Blue Double-Muscle Syndrome
Precision Nutritional Technology Combined with High Performance Exercise Physiology

Also see:

Big Blue Double-Muscle Syndrome

Sarcopenia -- The Role of Mitochondrial DNA (mt DNA) Deletion Mutation

Muscle Builder Myoplex®Induces Il-4

Definition of Myostatin

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