Alterations in diaphragm contractility after nandrolone administration: ananalysis of potential mechanisms

The aim of this study was to evaluate the potential mechanisms underlying t he improved contractility of the diaphragm (Dia) in adult intact male hamst ers after nandrolone (Nan) administration, given subcutaneously over 4 wk v ia a controlled-release capsule (initial dose: 4.5 mg kg(-1) day(-1); with weight gain, final dose: 2.7 mg kg(-1) day(-1)). Control (Ctl) animals rece ived blank capsules. Isometric contractile properties of the Dia were deter mined in vitro after 4 wk. The maximum velocity of unloaded shortening (V-o ) was determined in vitro by means of the slack test. Dia fibers were class ified histochemically an the basis of myofibrillar ATPase staining and fibe r cross-sectional area (CSA), and the relative interstitial space was quant itated. Ca2+-activated myosin ATPase activity was determined by quantitativ e histochemistry in individual diaphragm fibers. Myosin heavy chain (MHC) i soforms were identified electrophoretically, and their proportions were det ermined by using scanning densitometry. Peak twitch and tetanic forces, as well as V-o, were significantly greater in Nan animals compared with Ctl. T he proportion of type IIa Dia fibers was significantly increased in Nan ani mals. Nan increased the CSA of all fiber types (26-47%), whereas the relati ve interstitial space decreased. The relative contribution of fiber types t o total costal Dia area was preserved between the groups. Proportions of MH C isoforms were similar between the groups. There was a tendency for increa sed expression of MHC2B with Nan. Ca2+-activated myosin ATPase activity was increased 35-39% in all fiber types in Nan animals. We conclude that, afte r Nan administration, the increase in Dia specific force results from the r elatively greater Dia CSA occupied by hypertrophied muscle fibers, whereas the increased ATPase activity promotes a higher rate of crossbridge turnove r and thus increased V-o. We speculate that Nan in supraphysiological doses have the potential to offset or ameliorate conditions associated with enha nced proteolysis and disordered protein turnover.