ATTENUATION OF SKELETAL-MUSCLE WASTING WITH RECOMBINANT HUMAN GROWTH-HORMONE SECRETED FROM A TISSUE-ENGINEERED BIOARTIFICIAL MUSCLE

Skeletal muscle wasting is a significant problem in elderly and debili tated patients. Growth hormone (GH) is an anabolic growth factor for s keletal muscle but is difficult to deliver in a therapeutic manner by injection owing to its in vivo instability. A novel method is presente d for the sustained secretion of recombinant human GH (rhGH) from gene tically modified skeletal muscle implants, which reduces host muscle w asting. Proliferating murine C2C12 skeletal myoblasts stably transduce d with the rhGH gene were tissue engineered in vitro into bioartificia l muscles (C2-BAMs) containing organized postmitotic myofibers secreti ng 3-5 mu g of rhGH/day in vitro, When implanted subcutaneously into s yngeneic mice, C2-BAMs delivered a sustained physiologic dose of 2.5 t o 11.3 ng of rhGH per milliliter of serum. rhGH synthesized and secret ed by the myofibers was in the 22-kDa monomeric form and was biologica lly active, based on downregulation of a GH-sensitive protein synthesi zed in the liver. Skeletal muscle disuse atrophy was induced in mice b y hindlimb unloading, causing the fast plantaris and slow soleus muscl es to atrophy by 21 to 35% (p < 0.02). This atrophy was significantly attenuated 41 to 55% (p < 0.02) in animals that received C2-BAM implan ts, but not in animals receiving daily injections of purified rhGH (1 mg/kg/day). These data support the concept that delivery of rhGH from BAMs may be efficacious in treating muscle-wasting disorders.