Dec. 18, 2008

Blood-Vessel Narrowing May Explain Muscle Disease Fatigue

Missing or reduced levels of an enzyme known as neuronal nitric oxide synthase (nNOS) at its normal location on muscle-fiber membranes prevents blood vessels that supply active muscles from relaxing normally, leading to exercise-associated fatigue, says a team of researchers from the University of Iowa, the University of Michigan and the University of Washington School of Medicine.

The team published its findings online Oct. 26 in Nature. MDA supported Erik Rader at the University of Iowa for this work.

In normal skeletal muscle, nNOS is anchored to the membrane enclosing a muscle fiber via a cluster of proteins. When stimulated by active muscle, nNOS makes a signaling molecule called nitric oxide, which causes a cascade of effects that lead to relaxation of blood vessels and an increase in blood flow to active muscles.

When the protein cluster in the muscle-fiber membrane is disrupted, which occurs in Duchenne muscular dystrophy and type 2D limb-girdle muscular dystrophy, nNOS loses its anchor to the membrane, affecting signaling events downstream of the nitric oxide signaling pathway.

To probe the molecular basis of the exercise-induced fatigue common in people with muscle diseases, the researchers conducted a series of experiments in which they assessed post-exercise activity in mice with or without muscular dystrophy. Mice deficient in nNOS displayed fatigue after mild exercise.

Study results ruled out cardiac dysfunction, inflammation, pain, muscle damage and lack of muscle force as causes of the exercise-related fatigue, and suggested instead, that the faulty signaling pathway was caused by a loss of membrane-localized nNOS.

The team found a similar deficit in nNOS at the muscle-cell membrane in tissue samples from patients with a wide range of disorders, suggesting a shared mechanism of fatigue.

The investigators next either blocked the nNOS signaling pathway or caused vasoconstriction (blood-vessel narrowing) with drugs. Mice treated this way, although healthy, experienced fatigue after mild exercise similar to that experienced by the mice with muscular dystrophy or with deficient nNOS. This finding suggests that the absence of properly located nNOS leads to deficient signaling to blood vessels that feed active muscles, thus causing the fatigue after only mild exercise.

In further studies, the investigators eliminated the exaggerated fatigue response when they treated mice deficient for nNOS with a phosphodiesterase inhibitor, a drug that enhances the blood-vessel relaxation signal. (Sildenafil, or Viagra, is an example of this type of medication).