Metabolic myopathies are myopathies that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects that interfere with muscle's ability to create energy, causing a low ATP reservoir within the muscle cell.
At the cellular level, metabolic myopathies lack some kind of enzyme or transport protein that prevents the chemical reactions necessary to create adenosine triphosphate (ATP). ATP is often referred to as the "molecular unit of currency" of intracellular energy transfer. The lack of ATP prevents the muscle cells from being able to function properly. Some people with a metabolic myopathy never develop symptoms due to the body's ability to produce enough ATP through alternative pathways (e.g. the majority of those with AMP-deaminase deficiency are asymptomatic).
H2O + ATP → H+ + ADP + Pi + energy → muscle contraction
ATP is needed for muscle contraction by two processes:
Firstly, ATP is needed for transport proteins to actively transport calcium ions into the sarcoplasmic reticulum (SR) of the muscle cell between muscle contractions. Afterwards, when a nerve signal is received, calcium channels in the SR open briefly and calcium rushes into the cytosol by selective diffusion (which does not use ATP) in what is called a "calcium spark." The diffusion of calcium ions into the cytosol causes the myosin strands of the myofibril to become exposed, and the myosin strands pull the actin microfilaments together. The muscle begins to contract. Secondly, ATP is needed to allow the myosin to release and pull again, so that the muscle can contract further in what is known as the sliding filament model.
ATP is consumed at a high rate by contracting muscles. The need for ATP in muscle cells is illustrated by the phenomenon of Rigor mortis, which is the muscle rigidity that occurs in dead bodies for a short time after death. In these muscles, all the ATP has been converted to ADP, and in the absence of further ATP being generated, the calcium transport proteins stop pumping calcium ions into the sarcoplasmic reticulum and the calcium ions gradually leak out. This causes the myosin proteins to grab the actin and pull once but without further supply of ATP, cannot release and pull again. The muscles therefore remain rigid in the position at death until the binding of myosin to actin begins to break down and they become loose again.
Symptoms
In the event more ATP is needed from the affected pathway, the lack of it becomes an issue and symptoms develop. People with a metabolic myopathy often experience symptoms such as:
exercise intolerance, premature muscle fatigue, pain and cramping during and/or after exercise, heavy breathing, shortness of breath (dyspnea), or rapid breathing (tachypnea), inappropriate rapid heart rate in response to exercise (tachycardia), exaggerated cardiorespiratory (breath and heart rate combined) response to exercise (dyspnea/tachypnea and tachycardia), exercise-induced myogenic hyperuricemia (exercise-induced accelerated breakdown of purine nucleotides in muscle via adenylate kinase reaction and purine nucleotide cycle), transient muscle contracture or pseudomyotonia (like a really bad cramp that can last for hours, which is myogenic and EMG silent), progressive muscle weakness, may have a pseudoathletic appearance (hypertrophy or pseudohypertrophy) especially of the calves, myoglobinuria and considerable breakdown of muscle tissue (rhabdomyolysis).
The degree of symptoms varies greatly from person to person and is dependent on the severity of enzymatic or transport protein defect. In extreme cases it can lead to rhabdomyolysis. The symptoms experienced also depend on which metabolic pathway is impaired, as different metabolic pathways produce ATP at different time periods during activity and rest, as well as the type of activity (anerobic or aerobic) and its intensity (level of ATP consumption).
A majority of patients with metabolic myopathies have dynamic rather than static findings, typically experiencing exercise intolerance, muscle pain, and cramps with exercise rather than fixed muscle weakness. However, a minority of metabolic myopathies have fixed muscular weakness rather than exercise intolerance, imitating an inflammatory myopathy or limb girdle muscular dystrophy. It is uncommon that both static and dynamic signs predominate.
Types
Metabolic myopathies are generally caused by an inherited genetic mutation, an inborn error of metabolism. (In livestock, an acquired environmental GSD is caused by intoxication with the alkaloid castanospermine.) Metabolic myopathies cause the underproduction of adenosine triphosphate (ATP) within the muscle cell.