Age-related reductions in growth hormone (GH) and insulin-like growth factor-I (IGF-I) may contribute to decreased muscle mass and strength in older persons. The relationship of this phenomenon to skeletal muscle bioenergetics has not been reported. We sought to determine whether administration of GH-releasing hormone (GHRH) would sustain increases in GH and IGF-I and improve skeletal muscle function and selected measures of body composition and metabolism. We measured GH secretion, muscle strength, muscle histology, and muscle energy metabolism by phosphorus nuclear magnetic resonance spectroscopy (31P-NMRS), body composition, and endocrine-metabolic functions before and after 6 weeks of treatment. Eleven healthy, ambulatory, non-obese men aged 64 to 76 years with low baseline IGF-I levels were treated at home as outpatients by nightly subcutaneous self-injections of 2 mg GHRH for 6 weeks. We measured GH levels in blood samples obtained every 20 minutes from 8:00 PM to 8:00 AM; AM serum levels of IGF-I, IGF binding protein-3 (IGFBP-3), and GH binding protein (GHBP); muscle strength; muscle histology; the normalized phosphocreatine abundance, PCr/[PCr + Pi], and intracellular pH in forearm muscle by NMRS during both sustained and ramped exercise; body composition by dual-energy x-ray absorptiometry (DEXA); lipid levels; and glucose, insulin, and GH levels during an oral glucose tolerance test (OGTT). GHRH treatment increased mean nocturnal GH release (P < .02), the area under the GH peak ([AUPGH] P < .006), and GH peak amplitude (P < .05), with no change in GH pulse frequency or in levels of IGF-I, IGFBP-3, or GHBP Two of six measures of muscle strength, upright row (P < .02) and shoulder press (P < .04), and a test of muscle endurance, abdominal crunch (P < .03), improved. GHRH treatment did not alter exercise-mediated changes in PCr/[PCr + Pi] or intracellular pH, but decreased or abolished significant relationships between changes in PCr/[PCr + Pi] or pH and indices of muscle strength. GHRH treatment did not change weight, body mass index, waist to hip ratio, DEXA measures of muscle and fat, muscle histology, glucose, insulin, or GH responses to OGTT, or lipids. No significant adverse effects were observed. These data suggest that single nightly doses of GHRH are less effective than multiple daily doses of GHRH in eliciting GH- and/or IGF-I-mediated effects. GHRH treatment may increase muscle strength, and it alters baseline relationships between muscle strength and muscle bioenergetics in a manner consistent with a reduced need for anaerobic metabolism during exercise. Thus, an optimized regimen of GHRH administration might attenuate some of the effects of aging on skeletal muscle function in older persons.