dinoprost and Muscular-Atrophy

The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal.

Topics: Animals; Cachexia; Calcium; Cardiomegaly; Dinoprost; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Hydrogen Peroxide; Hyperaldosteronism; Male; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Muscle, Skeletal; Muscular Atrophy; Myocardium; Myocytes, Cardiac; Necrosis; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Ventricular Remodeling

Skeletal muscle recovery from disuse atrophy requires the recruitment of insulin signaling for muscle growth, which is driven by protein synthesis. Dietary fish oil, which is rich in long-chain n-3 polyunsaturated fatty acids, is known to enhance insulin signaling and protein metabolism. Therefore, this study was performed to evaluate whether dietary fish oil facilitates muscle recovery during remobilization after disuse atrophy. Ten days of immobilization, followed by 3 or 13 days of remobilization, were applied to the hindlimbs of rats fed corn oil [corn oil diet group as control (CO)] or fish oil [fish oil diet group (FO)] as source of dietary fat. The immobilization-induced reductions in soleus muscle weight and myosin heavy-chain content were significantly restored by 3 days of remobilization in CO. However, in FO, these muscle recovery measurements did not significantly change until 13 days of remobilization. At 3 days of remobilization, both groups had significant elevations in p70 ribosomal S6 kinase (p70s6k) activation and at a greater extent in CO than in FO. The activation of Akt was also increased on Day 3, but it was not significant in FO. Throughout the remobilization period, levels of prostaglandin F2α (PGF2α) and cyclooxygenase-2 mRNA were significantly augmented. However, FO had a lesser increase in PGF2α than CO until Day 13. These findings indicate that dietary fish oil inhibits the early stage of soleus muscle recovery after disuse atrophy by suppressing the activation of Akt-p70s6k signaling and PGF2α synthesis.

Topics: Animals; Base Sequence; Dietary Fats, Unsaturated; Dinoprost; DNA Primers; Enzyme-Linked Immunosorbent Assay; Fish Oils; Hindlimb Suspension; Male; Muscle, Skeletal; Muscular Atrophy; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases

Using stable-isotope techniques, we measured rates of quadriceps muscle protein synthesis in twelve women with sero-positive rheumatoid arthritis. The results were compared to those from the normal limb of seven women with unilateral osteoarthritis of the knee. Six patients had never received corticosteroid immuno-suppression, but the other six had taken an average of 8 mg Prednisolone per day for 9 years. Quadriceps atrophy was present in both sets of patients with rheumatoid arthritis (normal legs 444 +/- 182, rheumatoid 190 +/- 40, rheumatoid + steroid 300 +/- 110 micrograms protein/micrograms DNA, means +/- SD, both P less than 0.001). Muscle protein synthesis, calculated by comparing the incorporation of 13C-leucine into biopsy samples taken after an 8 h L-[1-13C] leucine infusion with the time averaged enrichment of blood alpha-ketoisocaproate, was 0.056 +/- 0.005% h-1 in the patients not receiving steroids compared with 0.050 +/- 0.02% h-1 in normals (P greater than 0.05) indicating that muscular atrophy was primarily due to an increase in rate of muscle protein breakdown. Intra-muscular PGE2 concentration was increased in these patients (rheumatoid 0.12 +/- 0.06 ng mg-1 tissue, normals 0.06 +/- 0.03 ng mg-1 tissue, P less than 0.05). Patients taking corticosteroids had a markedly depressed rate of muscle protein synthesis (0.035 +/- 0.008% h-1, P less than 0.05) and reduced intra-muscular PGF 2 alpha concentration (P less than 0.01). We conclude that steroid therapy significantly influences the mechanism of skeletal muscle atrophy in patients with rheumatoid arthritis.

Topics: Aged; Arthritis, Rheumatoid; Dinoprost; Female; Humans; Middle Aged; Muscle Proteins; Muscles; Muscular Atrophy; Prednisolone