Subcellular effects of myocyte-specific androgen receptor overexpression in mice

Abstract

Although androgen receptor (AR) within myocytes is thought to mediate many of the effects of testosterone and other androgens on skeletal muscle, little is known about the functions of AR within these cells. We, therefore, studied the ultrastructure of skeletal muscle of HSA-AR transgenic (Tg) mice that overexpress AR selectively in myocytes and exhibit neuromuscular atrophy. We examined male HSA-AR mice from two different founding lines: L78 (lower copy number and less severe phenotype) and L141 (higher copy number and more severe phenotype) and compared these to wild-type (Wt) brothers. We also examined testosterone-treated female mice from these two lines and compared them both to their Wt sisters and to vehicle-treated controls. Ultrastructural examination of extensor digitorum longus sections using transmission electron microscopy revealed remarkably disorganized myofibrils in male Tg and testosterone-treated female Tg mice. Quantification of ultrastructural pathology indicated reduced myofibril width, hypertrophic and hyperplastic intermyofibrillar mitochondria, and pronounced glycogen accumulation in HSA-AR males of both lines. Reduced myofibrillar width and increases in mitochondrial number, size, and volume density were also observed in testosterone-treated HSA-AR females, although glycogen accumulation was not observed. Structural abnormalities in mitochondria were also associated with increases in electron transport chain activity and systemic resting metabolic rate, indicative of hypermetabolism. We find that overexpression of AR in myocytes of HSA-AR mice results in alterations in myofibrils, mitochondria, and glycogen. Alterations in myofibrils and mitochondria appear to result from acute actions of testosterone, whereas those on glycogen do not. Pathology of myofibrils and/or mitochondria may, therefore, mediate in part the neuromuscular atrophy observed in HSA-AR mice.

Androgen receptors in muscle fibers induce rapid loss of force but not mass: Implications for spinal bulbar muscular atrophy

“…We also found that fatigue resistance was reduced in the EDL, but not in the SOL, after 5 days of T treatment in Tg mice, with no effects on fatiguability at 3 days (Fig 6). Interestingly, other investigators studying the same model report that the number and size of mitochondria in the EDL increases significantly after a week of T exposure, 34 suggestive of mitochondrial dysfunction. While the EDL normally derives much of its ATP from glycolytic metabolism, the EDL from female Tgs after 9 days of T has shifted to a more oxidative metabolism based on NADH staining.…”

“…In our model, loss of muscle function is associated with both an increase in mitochondrial number and activity of complexes I, II and IV in the respiratory chain of mitochondria. 34 These mitochondrial complexes are the primary source of reactive nitrogen and oxygen. Paradoxically, the production of ATP may at the same time be decreasing, as suggested by the reduced resistance to fatigue in the EDL and a deficit in citric synthase activity found in the fast twitch muscle anterior tibialis of these same T-treated Tg mice (unpublished observation).…”

Exposure to AT1 Receptor Autoantibodies during Pregnancy Increases Susceptibility of the Maternal Heart to Postpartum Ischemia-Reperfusion Injury in Rats

“…For each subject, five micrographs were sampled to obtain measurements of sarcomere width (short axis) and length (long axis), mitochondrial volume density, numerical density, and mean volume were measured as described previously. Measurements of sarcomere width were performed on eight sarcomeres per photomicrograph [28]. …”

Turning sex inside-out: Peripheral contributions to sexual differentiation of the central nervous system

“…Over-expression of AR within myocytes does indeed increase myocyte size, but curiously, it is also sufficient to decrease adipose tissue [64]. Because these alterations in body composition were associated with changes in resting metabolic rate, muscle respiration, and, in mice, alterations in mitochondrial morphology, these results are most obviously consistent with an endocrine mechanism of action [64,65]. It therefore remains possible, but it seems less likely, that endocrine mechanisms explain the effect of myocyte AR on spinal motoneurons.…”