Randomized control trial to evaluate the effects of acute testosterone administration in men on muscle mass, strength, and physical function following ACL reconstructive surgery: rationale, design, methods

Brian W Wu, Max Berger, Jonathan C Sum, George F Hatch 3rd, E Todd Schroeder, Brian W Wu, Max Berger, Jonathan C Sum, George F Hatch 3rd, E Todd Schroeder

Abstract

Background: The anterior cruciate ligament (ACL) is one of four major ligaments in the knee that provide stability during physical activity. A tear in the ACL is characterized by joint instability that leads to decreased activity, knee dysfunction, reduced quality of life and a loss of muscle mass and strength. While rehabilitation is the standard-of-care for return to daily function, additional surgical reconstruction can provide individuals with an opportunity to return to sports and strenuous physical activity. Over 200,000 ACL reconstructions are performed in the United States each year, and rehabilitation following surgery is slow and expensive. One possible method to improve the recovery process is the use of intramuscular testosterone, which has been shown to increase muscle mass and strength independent of exercise. With short-term use of supraphysiologic doses of testosterone, we hope to reduce loss of muscle mass and strength and minimize loss of physical function following ACL reconstruction compared to standard-of-care alone.

Methods/design: This study is a double-blinded randomized control trial. Men 18-50 years of age, scheduled for ACL reconstruction are randomized into two groups. Participants randomized to the testosterone group receive intramuscular testosterone administration once per week for 8 weeks starting 2 weeks prior to surgery. Participants randomized to the control group receive a saline placebo intramuscularly instead of testosterone. Lean mass, muscle strength and physical function are measured at 5 time points: 2 weeks pre-surgery, 1 day pre-surgery, and 6, 12, 24 weeks post-surgery. Both groups follow standard-of-care rehabilitation protocol.

Discussion: We believe that testosterone therapy will help reduce the loss of muscle mass and strength experienced after ACL injury and reconstruction. Hopefully this will provide a way to shorten the rehabilitation necessary following ACL reconstruction. If successful, testosterone therapy may also be used for other injuries involving trauma and muscle atrophy.

Trial registration: NCT01595581, REGISTRATION: May 8, 2012.

Figures

Figure 1
Figure 1
Akt1 signaling and control of skeletal muscle hypertrophy and atrophy. Anabolic signals (e.g. testosterone) initiate phosphorylation (P) of Akt1, which activates protein synthesis via the mTOR pathway. At the same time, Akt1(P) inactivates FOXO3a by phosphorylation and facilitates translocation of FOXO3a out of the nucleus, resulting in inhibition of the atrophy-related genes (atrogens), and thereby decreasing protein degradation. On the other hand, catabolic stimuli (e.g. glucocorticoids) dephosphorylate and thereby inactivate the Akt1 protein. Inactivation of the Akt1 protein allows expression of FOXO3a in the nucleus and subsequent activation of the atrogens, resulting in protein degradation. (Figure adapted from G.A. Nader) [10].

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Pre-publication history
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