Anabolic-androgenic steroids (AAS), such as testosterone, are used to increase mass and strength. Clinically, they are used to treat hypogonadism, age-related decrements in muscle function, AIDS-related muscle wasting and, muscle wasting associated with chronic obstructive pulmonary disease (COPD). Pharmacologic AAS treatment is effective in decreasing diaphragm (DIA) fatigue during direct muscle stimulation in female rats. Identical AAS treatment of male rats had no effect on DIA muscle fatigue using the same stimulation paradigm. Peripheral muscle fatigue can result from failure in neuromuscular transmission, excitation-contraction coupling, or contraction. The contribution of neurotransmission failure to muscle fatigue cannot be determined using direct muscle stimulation. Preliminary results suggest that chronic testosterone treatment of sedentary adult male rats decreases DIA fatigue during repetitive nerve stimulation, decreases the contribution of neuromuscular transmission to DIA fatigue, selectively improves neuromuscular transmission of type 2X and 2B DIA fibers and, also selectively increases axon terminal and motor endplate size at the neuromuscular junction of type 2X and 2B DIA fiber. We have previously shown that testosterone treatment increases the steady-state levels of choline acetyltransferase (ChAT) mRNA in motoneurons of the lateral motor columns of the cervical and lumbar spinal cord. These data suggest that testosterone may modulate the expression of proteins essential to synaptic transmission at the neuromuscular junction. The goal of this research proposal is to test the hypothesis that testosterone decreases peripheral muscle fatigue through the improvement of neuromuscular transmission in the rat DIA. Indeed, improved neuromuscular transmission may underlie the effects of AAS on muscle function. The four specific aims will be addressed in four experiments and provide data to test this hypothesis. Experiment I will determine the effects of pharmacologic testosterone treatment on neuromuscular transmission failure to peripheral DIA fatigue. Experiment II will determine the correlation between developmental testosterone fluctuations during postnatal development and DIA fatigue. Experiment III will examine the effect of pharmacologic testosterone treatment on synaptic transmission and neuromuscular junction morphology in the DIA muscle. Finally, the ability of testosterone to regulate ChAT and vesicular acetylcholine transporter mRNA levels in phrenic motoneurons and mRNA levels for the alpha-subunit of the nicotinic acetylcholine receptor subunit (alpha-AchR) in the DIA muscle will be determined in Experiment IV.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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Twery, Michael
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University of Southern California
Schools of Dentistry
Los Angeles
United States
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Blanco, C E; Davenport, T; Wachi, S et al. (2001) Androgen receptor immunoreactivity of male rat cervical motor neurons is increased by chronic pharmacologic testosterone treatment. Acta Physiol Pharmacol Bulg 26:7-10
Blanco, C E; Zhan, W Z; Fang, Y H et al. (2001) Exogenous testosterone treatment decreases diaphragm neuromuscular transmission failure in male rats. J Appl Physiol 90:850-6