Understanding Neuromuscular Weakness of Acute Organophosphate Poisoning: The Significance of Metabolic Energy, Muscle Protein Degradation and Amino Acids

Organophosphate compounds, among the largest class of pesticides manufactured and used worldwide, are common agents for intentional self-harm in agricultural communities of Asia and Africa. Organophosphates inhibit acetylcholinesterase and cause muscle weakness. Delayed paralysis that occur s 24 to 48 hours after severe organophosphate poisoning and which can last for 1 to 3 weeks is the main cause of morbidity and mortality in Indian patients. The pathophysiology that underlies this delayed, persistent muscle weakness is not clear but would be useful to elucidate and improve treatment. This study examines mechanisms that contribute to skeletal muscle weakness that occurs in acute organophosphate pesticide poisoning. The study specifically explores whether low muscle acetylcholinesterase activity in conjunction with insufficient metabolic energy for contraction and increased degradation of muscle proteins contribute to muscle weakness induced by acute severe monocrotophos poisoning. Rats were subject to acute monocrotophos poisoning (0.8LD50) and the course of poisoning evaluated by cholinergic symptoms and skeletal muscle weakness was correlated to muscle acetylcholinesterase activity, metabolic energy levels and breakdown of muscle proteins. Metabolic energy available for muscle contraction was estimated by levels of plasma glucose, controlled by gluconeogenesis, insulin, the pancreas and corticosteroids, and by branched chain amino acids in the muscle. Protein degradation in the muscle , in response to metabolic acidosis as a catabolic stimulus, was determined by amino acids in muscle, blood and urine , ubiquitinylated proteins and myosin-actin stoichiometry in the muscle . Plasma creatine kinase was the index of injury to the muscle. Monocrotophos poisoning rapidly led to muscle injury and progressive muscle weakness in rats accompanied by 75% inhibition of muscle acetylcholinesterase, and hyperglycemia, because of pancreatic injury that lowered insulin secretion. Degradation of muscle proteins through the ubiquitin - proteasome pathway possibly stimulated by metabolic acidosis, with sparing of the actinomyosin complex, characterized muscle weakness in the early phase of poisoning. Rats recovered from muscle weakness within 24 hours with no treatment. Recovery of muscle strength was characterized by a) recovery of muscle acetylcholinesterase activity to 40% of normal, b) normoglycemia by recovery of the pancreas and normal insulin secretion, c) Decrease in degradation of muscle proteins, although muscle injury persisted, d) Recovery of muscle strength was associated with increase of branched chain amino acids in muscle and sustained increase of plasma glucogenic amino acids. Severe inhibition of muscle acetylcholinesterase, inadequate supply of metabolic energy substrate to the muscle and degradation of muscle proteins accompany muscle weakness of rats acutely poisoned with monocrotophos. Recovery of muscle strength in these animals required prevention of persistent inhibition of acetylcholinesterase at the neuromuscular junction, normoglycemia and protection of muscle proteins , especially the contractile proteins, from degradation. Interventions that address metabolic energy insufficiency and protein degradation in muscle may reduce the duration and adverse outcome of muscle weakness in organophosphate poisoned patients