cyclic-gmp and Muscular-Diseases

Topics: Adiponectin; Adult; Amino Acid Sequence; Animals; Autoantibodies; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Muscular Diseases; Nitric Oxide; Pregnancy; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction; Vasodilation; Young Adult

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown. With no treatment available, this form of inactivity is a major determinant of disability. Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Edema; Enzyme Activation; Exercise; Fatigue; Hemodynamics; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Skeletal; Muscular Diseases; Nitric Oxide; Nitric Oxide Synthase Type I; Phosphodiesterase 5 Inhibitors; Protein Transport; Sarcolemma; Signal Transduction

The properties and distribution of basal and cyclic nucleotide stimulated protein kinases have been studied in normal and diseased human muscles. In particulate fraction of muscles from neurogenic atrophy the PK activity is remarkably lower than in control tissues, whereas in the cytosol of the same tissues an increase of enzyme activity was observed. In Duchenne dystrophy the PK activities were slighly lower than in controls both in particulate and in soluble fractions. The authors suggest that the altered subcellular distribution found in neurogenic atrophy might be due to the loss of nerve trophic control.

Topics: Cyclic AMP; Cyclic GMP; Cytosol; Humans; Kinetics; Mitochondria, Muscle; Muscles; Muscular Atrophy; Muscular Diseases; Muscular Dystrophies; Protein Kinases; Subcellular Fractions

Guanylate cyclase activity has been studied in muscle of normal subjects and of patients suffering from muscular and neuromuscular diseases. In normal tissue a guanylate cyclase activity was found in both soluble and particulate fractions of homogenate. We found also that the kinetic analysis of the enzyme of soluble differed from that of particulate fraction. A decrease of guanylate cyclase activity in crude homogenate was observed in muscular dystrophies, in neuromuscular atrophies, and in inflammatory forms of muscle disease.

Topics: Cyclic GMP; Guanylate Cyclase; Humans; Mitochondria, Muscle; Muscles; Muscular Atrophy; Muscular Diseases; Muscular Dystrophies; Myasthenia Gravis; Myositis

Topics: Cyclic AMP; Cyclic GMP; Humans; Muscles; Muscular Diseases; Muscular Dystrophies; Phosphoric Diester Hydrolases