Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity.

c-Jun NH(2)-terminal kinase (JNK) is highly expressed in skeletal muscle and is robustly activated in response to muscle contraction. Little is known about the biological functions of JNK signaling in terminally differentiated muscle cells, although this protein has been proposed to regulate insulin-stimulated glycogen synthase activity in mouse skeletal muscle. To determine whether JNK signaling regulates contraction-stimulated glycogen synthase activation, we applied an electroporation technique to induce JNK overexpression (O/E) in mouse skeletal muscle. Ten days after electroporation, in situ muscle contraction increased JNK activity 2.6-fold in control muscles and 15-fold in the JNK O/E muscles. Despite the enormous activation of JNK activity in JNK O/E muscles, contraction resulted in similar increases in glycogen synthase activity in control and JNK O/E muscles. Consistent with these findings, basal and contraction-induced glycogen synthase activity was normal in muscles of both JNK1- and JNK2-deficient mice. JNK overexpression in muscle resulted in significant alterations in the basal phosphorylation state of several signaling proteins, such as extracellular signal-regulated kinase 1/2, p90 S6 kinase, glycogen synthase kinase 3, protein kinase B/Akt, and p70 S6 kinase, in the absence of changes in the expression of these proteins. These data suggest that JNK signaling regulates the phosphorylation state of several kinases in skeletal muscle. JNK activation is unlikely to be the major mechanism by which contractile activity increases glycogen synthase activity in skeletal muscle.

Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones.

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/loxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.

Dietary protein adequacy and lower body versus whole body resistive training in older humans.

This study assessed the effects of long-term consumption of the United States Recommended Dietary Allowance (RDA) for protein by older people who were sedentary or performed resistive training (RT) on body composition, skeletal muscle size and protein metabolism, and if the number of muscle groups trained influenced the muscle hypertrophy response to RT. Twelve men and 17 women (age range 54-78 years) completed this 14 week controlled diet and exercise study. Throughout the study, each subject completely consumed daily euenergetic menus that provided the RDA of 0.8 g protein kg(-1) day(-1). From study weeks 3-14 (weeks RT1-RT12), 10 subjects (four men, six women) performed whole body RT (WBRT), nine subjects (four men, five women) performed lower body RT (LBRT) and 10 subjects (four men, six women) remained sedentary (SED). Both the LBRT and WBRT groups performed knee extension and flexion exercises, and the WBRT group also performed chest press and arm pull exercises (three sets per exercise at 80 % of one repetition maximum, 3 days per week for 12 weeks). From week 2 (baseline) to week RT12, muscle strength increased in muscle groups trained in the LBRT and WBRT groups, and was not changed in the SED group. From baseline to week RT12, whole body muscle mass and protein-mineral mass were not changed, fat-free mass (P = 0.004) and total body water (P = 0.013) were decreased, and percentage body fat was increased (P = 0.011) in these weight-stable older people, independent of group assignment. The RT-induced increases in mid-thigh muscle area (from computed tomography scans) were comparable in the LBRT and WBRT groups (2.13 +/- 1.26 cm(2) and 2.17 +/- 1.24 cm(2), respectively), and were different from those in the SED group, which lost muscle area (-1.74 +/- 0.57 cm(2); group-by-time P < 0.05). From baseline to week RT12, 24 h urinary total nitrogen excretion decreased (P < 0.001), nitrogen balance shifted from near equilibrium to positive, whole body leucine oxidation (from the infusion of L-[(13)C]leucine) decreased (P < 0.05) and net (postabsorptive vs. postprandial) leucine balance (P < 0.05) increased from near equilibrium to positive, with no differences in responses over time among the three groups. In conclusion, the number of muscle groups trained did not influence whole body protein metabolism or RT-induced muscle hypertrophy in older people. Most of these data are consistent with a successful adaptation to the RDA for protein. However, research should continue to question whether the decreases in fat-free mass and total body water observed in all subjects, and the decrease in mid-thigh muscle area in the SED group, are physiological accommodations, and whether the RDA for protein might be marginally inadequate for older people to maintain skeletal muscle.