Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals.

BACKGROUND: Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP) and congestive heart failure (CHF) as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R) agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting. HYPOTHESIS: We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals. METHODS: We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP. RESULTS: In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL) force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals. CONCLUSIONS: These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production.

PKC translocation and ERK1/2 activation in compensated right ventricular hypertrophy secondary to chronic emphysema.

BACKGROUND: Right ventricular hypertrophy (RVH) is an important complication of chronic lung disease. However, the signal transduction pathways involved as well as the physiological changes to the right ventricle have not been investigated. Emphysema was produced in male, Syrian Golden hamsters by intra-tracheal instillation of 250 IU/kg elastase (Emp, n = 17). Saline treated animals served as controls (Con, n = 15). RESULTS: Nine months later, Emp hamsters had 75% greater lung volume, and evidence of RVH at the gross and myocyte level (RV:tibia length Emp 6.84 +/- 1.18 vs. Con 5.14 +/- 1.11 mg/mm; myocyte cross sectional area Emp 3737 vs. Con 2695 microm2), but not left ventricular hypertrophy. Serial echocardiographic analysis from baseline to nine months after induction of emphysema revealed increasing right ventricular internal dimension and decreased pulmonary artery acceleration time only in Emp hamsters. There was an increase in translocation of PKC betaI and PKC epsilon from cytosolic to membranous cell fractions in RV of Emp hamsters. Phosphorylation of PKC epsilon was unchanged. Translocation of PKC alpha and betaII were unchanged. Emp animals had a 22% increase in phospho-ERK 1/2, but no change in levels of total ERK 1/2 compared to Con. CONCLUSION: These data suggest that PKC betaI, epsilon and ERK 1/2 may play a role in mediating compensated RVH secondary to emphysema and may have clinical relevance in the pathogenesis of RVH.

Emphysema-induced reductions in locomotory skeletal muscle contractile function.

Patients with COPD suffer from locomotory skeletal muscle contractile dysfunction. This may be due to the disease per se or as a result of some confounding factor. Therefore, the purpose of this investigation was to determine whether emphysema: (1) reduces force production; (2) increases fatigability; and (3) impairs the speed of recovery in locomotory skeletal muscle in an accepted animal model in which many confounding variables can be controlled. To explore this issue, in situ mechanical properties of gastrocnemius were measured in Syrian Golden hamsters 8 months after intratracheal instillation of either saline (control, n = 5) or elastase (emphysema, n = 7). Emphysema increased excised lung volume (80%; P < 0.01), increased fatigability (control, 25% reduction in maximal strength after 4 min of repeated contractions; emphysema, 55% reduction; P < 0.05) and decreased the recovery rate (half-times of recovery: control, 7 +/- 7 s; emphysema, 92 +/- 92 s; P < 0.05) of gastrocnemius muscle. In contrast, emphysema had no effect on maximal force, whether related to body mass or muscle mass, or force-velocity characteristics of gastrocnemius muscle. These data demonstrate that emphysema, independent of physical activity levels, pharmacological intervention, and/or nutritional status, can increase fatigability and impair the speed of recovery of locomotory skeletal muscle contractile function which may contribute to exercise intolerance of COPD patients.

Cortical bone dynamics, strength, and densitometry after induction of emphysema in hamsters.

Recent evidence suggests that patients suffering from chronic obstructive pulmonary disease are also at an increased risk of developing osteoporosis. The pathophysiological mechanism(s) linking these progressive diseases is unknown. The goal of this investigation was to determine whether there were alterations in bone mineral density and content, cortical bone structure and strength, and indexes of bone formation and resorption in the elastase-induced emphysematous hamster. At 3 wk after induction of emphysema, the femoral bone mineral content was 8% less (P = 0.026) and the femoral fracture strength was 6% less (P = 0.032) in the emphysematous hamster than in controls. The cortical area was 8.4% less (P = 0.013) and the periosteal mineral appositional rate was 27% less (P = 0.05) than in controls. Additionally, the endocortical eroded surface in the emphysematous group was about twice that in the control group (P = 0.003). Differences in some indexes of bone formation and resorption, paralleled by differences in bone structure and strength, were observed 3 wk after induction of emphysema. These differences in skeletal metabolism and strength may help explain some of the skeletal changes associated with chronic obstructive pulmonary disease in humans.

Fiber composition and oxidative capacity of hamster skeletal muscle.

The hamster is a valuable biological model for physiological investigation. Despite the obvious importance of the integration of cardiorespiratory and muscular system function, little information is available regarding hamster muscle fiber type and oxidative capacity, both of which are key determinants of muscle function. The purpose of this investigation was to measure immunohistochemically the relative composition and size of muscle fibers composed of types I, IIA, IIX, and IIB fibers in hamster skeletal muscle. The oxidative capacity of each muscle was also assessed by measuring citrate synthase activity. Twenty-eight hindlimb, respiratory, and facial muscles or muscle parts from adult (144-147 g bw) male Syrian golden hamsters (n=3) were dissected bilaterally, weighed, and frozen for immunohistochemical and biochemical analysis. Combining data from all 28 muscles analyzed, type I fibers made up 5% of the muscle mass, type IIA fibers 16%, type IIX fibers 39%, and type IIB fibers 40%. Mean fiber cross-sectional area across muscles was 1665 +/- 328 microm(2) for type I fibers, 1900 +/- 417 microm(2) for type IIA fibers, 3230 +/- 784 microm(2) for type IIX fibers, and 4171 +/- 864 microm(2) for type IIB fibers. Citrate synthase activity was most closely related to the population of type IIA fibers (r=0.68, p<0.0001) and was in the rank order of type IIA > I > IIX > IIB. These data demonstrate that hamster skeletal muscle is predominantly composed of type IIB and IIX fibers.

Lipid peroxidation in the skeletal muscle of hamsters with emphysema.

Current evidence suggests that skeletal muscle functional impairments present in emphysema and COPD patients may in part be a consequence of the disease condition per se. The mechanistic basis for these impairments is uncertain. Within the human population, it is difficult to control for confounding effects of concomitantly reduced activity levels. To explore this issue, malondialdehyde (MDA), a marker of lipid peroxidation, and enzymes of the glutathione redox system were measured in selected hindlimb muscles of Syrian Golden hamsters 6 months following intratracheal instillation of either saline (CON, n=7) or elastase (25 U/100 g body weight, EMP, n=5) in an accepted model where physical activity levels between control and EMP groups could be equated. Excised lung volume increased with EMP (CON, 1.3+/-0.2 g; EMP, 3.2+/-0.4 g, P<0.01). MDA was increased in the gastrocnemius (CON, 238+/-87; EMP, 371+/-122 nmol/g protein, P<0.05) of EMP hamsters. Antioxidant concentrations had a disparate response; glutathione (CON, 7.68+/-1.53; and EMP, 10.25+/-0.67 &mgr;mol/g protein, P<0.01) and the activity of glutathione reductase (GR) were increased (CON, 1.87+/-0.17; and EMP, 2.46+/-0.31 U/g protein, P<0.01) in the gastrocnemius, whereas the activity of glutathione peroxidase (GPx) was decreased (CON, 12.7+/-2.65; and EMP, 9.46+/-1.88 U/g protein, P<0.05) in the vastus lateralis of EMP hamsters. CONCLUSION: These data indicate that EMP may induce oxidative stress in peripheral skeletal muscle.