1. Growth hormone-deficient hypopituitary adults often complain of weakness and fatigue. The cause of the fatigue is unknown but could be an increased proportion of fast, fatiguable, type 2 fibres in the muscle. The aim of this study was to examine the contractile properties of the quadriceps muscle in a group of these patients compared with healthy controls. Changes in these properties were also examined in a small subset of the patients following growth hormone replacement. 2. Isometric strength, half-relaxation time from a twitch (t1/2) and the force-frequency relationship were measured using electrically evoked contractions in 14 growth hormone-deficient patients and 14 age- and sex-matched controls. Six patients were restudied following 6-24 month's replacement therapy with growth hormone (daily dose 0.04 +/- 0.01 i.u./kg). 3. The growth hormone-deficient patients had a significantly lower t1/2 than the controls (46.1 +/- 6.1 ms versus 56.1 +/- 10.5 ms respectively; P = 0.0072; mean +/- SD). The 10/100% ratio was also significantly lower in growth-hormone-deficient patients (38.6 +/- 9.9% versus 52.3 +/- 8.0%; P = 0.0005), as was muscle strength (349 +/- 99 N versus 493 +/- 215 N; P = 0.036). Following growth hormone replacement, muscle strength increased significantly (P < 0.05). The 10/100% ratio also increased towards control values, but this change was not significant. 4. These results demonstrate that the relaxation times of the quadriceps are significantly shorter and that the force-frequency relationship shifted to the right in growth hormone-deficient patients, which is consistent with a greater proportion of type 2 fibres within the muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases (Msr) reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA−/−) are prone to the development of high fat diet-induced insulin resistance and a reduced physiological insulin response compared to high fat-fed wild type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high fat-fed mice show similar reduction in insulin receptor function and the lack of MsrA further diminishes these functions. Together, these data demonstrate for the first time that MsrA plays a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation.