Abstract
The signaling pathway responsible for muscle hypertrophy following testosterone replacement therapy (TRT) and resistance training (RT) has not been elucidated after spinal cord injury (SCI). Furthermore, it is unclear whether evoking muscle hypertrophy improves mitochondrial citrate synthase activity (CS) and Complex III (CIII) activities after SCI. PURPOSE: To examine the effects of TRT+RT compared to TRT only on protein expression of markers associated with muscle hypertrophy, substrate utilization and mitochondrial biogenesis in men with SCI. METHODS: Twenty-two men with motor complete SCI were randomized to 16 weeks of TRT+RT or TRT only. Evoked progressive RT using neuromuscular electrical stimulation (2 lb. increments) was administered twice weekly. TRT patches (2-6 mg/day) were applied at bedtime. Muscle biopsies were captured before and after 16 weeks from the right vastus lateralis. Protein expression of markers associated with muscle hypertrophy were evaluated [FAK, total and phosphorylated Akt, total and phosphorylated mTOR] and substrate utilization and mitochondrial biogenesis [GLUT4, PGC1α, total and phosphorylated AMPK]. Mitochondrial CS and CIII activity were also measured. RESULTS: TRT+RT demonstrated a 27.5% increase (P=0.01) in average fiber CSA compared to -9% decrease following TRT only. Circulating IGFBP-3 increased (P=0.0001) in both TRT+RT (1764±665 to 2548.5±853 ng/ml) and TRT (1918.5±587 to 2778±967 ng/ml). GLUT4 was elevated in the TRT+RT group compared to the TRT only (P=0.005). Total Akt (P=0.06) and phosphorylated Akt^Ser389 (P=0.049) were also elevated in the TRT+RT group. Mitochondrial CS (34% P=0.006) increased in the TRT+RT group. CONCLUSION: Sixteen weeks of TRT+RT resulted in hypertrophy of myofibers that was associated with increased protein expression and markers of activation of Akt. This was further associated with elevations in GLUT4 protein expression and markers of mitochondrial function in persons with SCI.
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