Neuromuscular fatigue

Pain, muscular weakness, cramps and ease of fatigue are the most usual symptoms of muscular disease. In most cases, it is diseases of the vascular or nervous system or problems with the processes providing energy within the muscle that are responsible for clinical problems with muscles. Other clinical problems include the muscular dystrophies, myotonic disorders, inflammatory myopathies and disorders of neuromuscular transmission (see Walton, 1996). The best known is Duchenne muscular dystrophy. 

ACh receptors are destroyed by endocytosis via coated pits and proteolysis in lysosomes. In myasthenia gravis, the receptors are crosslinked by antireceptor antibodies, which facilitate the rate-limiting endocytosis step receptor destmction occurs in less than half the normal time, resulting in net receptor loss. The chronic disease is characterized clinically by such muscular weakness and abnormal fatigue that patients cannot even keep their eyes open. Acetylcholinesterase inhibitors increase the ACh concentration and excitation of the neuromuscular junction, resulting in increased strength and endurance. As expected, AChE inhibitors are also potent curare antidotes because the increased ACh levels displace the blocker more readily. 

Neostigmine is a drug of choice in the treatment of myasthenia gravis, a chronic disease characterized by muscular weakness and rapid fatiguability of the skeletal muscles due to impaired neuromuscular transmission. The defect may be presynaptic or postsynaptic. 

Belluardo, N., Westerblad, H., Mudo, G., Casabona, A., Bruton, J., Caniglia, G., et al. (2001) Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Mol Cell Neurosci 18, 56-67. 

Myasthenia gravis (literally serious muscle-weakness ), a neuromuscular disease leading to fluctuating muscle weakness and fatigue (see below). 

For some patients, cessation of tryptophan ingestion led to resolution of the symptoms in other patients the use of high dose corticosteroids appeared to be helpful. However, for some patients, the disease evolved into a chronic phase, with cutaneous, neuromuscular, pulmonary, cardiac, and cognitive involvement. The most common features of chronic EMS are fatigue, muscle cramping, myalgia, paraesthesias with objectively demonstrated hypes-thesias (lessened sensitivity to touch), chronic joint pain, scleroderma-like skin changes, and proximal muscle weakness. In one study, 88% of EMS patients continued to manifest more than three of these clinical symptoms after 3 years. 

HYPERCALCEMIA The degree and rapidity of onset of hypercalcemia largely dictate the extent of symptoms. Chronic elevation of serum Ca to 12-14 mg/dL (3-3.5 mM) generally causes few manifestations, whereas an acute rise to the same level may cause marked neuromuscular manifestations by increasing the threshold for nerve and muscle excitation. Symptoms include fatigue, weakness, anorexia, depression, diffuse abdominal pain, and constipation. 

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