Inactivation of AMPK alpha 1 Induces Asthenozoospermia and Alters Spermatozoa Morphology

AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, is present in metabolic tissues (muscle and liver) and has been identified as a modulator of the female reproductive functions. However, its function in the testis has not yet been clearly defined. We have investigated the potential role of AMPK in male reproduction by using transgenic mice lacking the activity of AMPK catalytic subunit alpha 1 gene [alpha 1AMPK knockout (KO)]. In the testis, the alpha 1AMPK subunit is expressed in germ cells and also in somatic cells (Sertoli and Leydig cells). alpha 1AMPK KO male mice show a decrease in fertility, despite no clear alteration in the testis morphology or sperm production. However, in alpha 1AMPK(-/-) mice, we demonstrate that spermatozoa have structural abnormalities and are less motile than in control mice. These spermatozoa alterations are associated with a 50% decrease in mitochondrial activity, a 60% decrease in basal oxygen consumption, and morphological defects. The alpha 1AMPK KO male mice had high androgen levels associated with a 5- and 3-fold increase in intratesticular cholesterol and testosterone concentrations, respectively. High concentrations of proteins involved in steroid production (3 beta-hydroxysteroid dehydrogenase, cytochrome steroid 17 alpha-hydroxylase/17,20 lysate, and steroidogenic acute regulatory protein) were also detected in alpha 1AMPK(-/-) testes. In the pituitary, the LH and FSH concentrations tended to be lower in alpha 1AMPK(-/-) malemice, probably due to the negative feedback of the high testosterone levels. These results suggest that total alpha 1AMPK deficiency in male mice affects androgen production and quality of spermatozoa, leading to a decrease in fertility. (Endocrinology 153: 3468-3481, 2012