Muscular Dystrophy

Introduction. First, we will give a general overview of the generation of muscle contraction in a normal cell. Skeletal muscle contraction is accomplished by the generation of a neuronal action potential that terminates at the neuromuscular synapse. The neuronal action potential (AP) stimulates sodium channels in the neuronal axon that propagates the signal along the axon. As the AP reaches the end of the axon, voltage gated calcium channels are activated which allows the influx of calcium into the neuron. This influx of calcium, in turn, stimulates the release of a neurotransmitter, acetylcholine, from the nerve terminal into the synapse. The acetylcholine binds to receptors on the cell surface of the postsynaptic cell, the muscle in this case. Binding of the acetylcholine to its receptors allows influx of sodium into the muscle, generates a new AP that propagates a transmembrane signal that spreads along the membrane of the cell. The AP is carried from the cell surface into the interior of the cell by a series of invaginations of the cell membrane known as T-tubules. These structures allow for transmembrane electrical depolarizations to be carried deeply within the cell where they would otherwise not be generated. At the ends of the T-tubules the sodium currents are again replaced by calcium currents, resulting from the activation of a voltage gated calcium channel known as the dihydropyridine receptor. These calcium currents, in their turn, stimulate larger calcium release from the sarcoplasmic reticulum through a calcium-sensitive calcium channel, the ryanodine receptor. These larger fluxes of calcium stimulate movement of the actin-myosin filaments, an ATP requiring step (and therefore dependent on functioning mitochondria). The filaments are attached to the surface of the muscle and the surrounding matrix through a variety of proteins, most notably dystrophin. Movement of the filaments is transduced into shortening of the cell (muscle contraction) by the connection to the cell surface and surrounding matrix. Relaxation is accomplished by reuptake of the intracellular calcium primarily back into the sarcoplasmic reticulum. This reuptake is energy requiring and dependent on ATP-dependent calcium pumps. Since reuptake of calcium is energy requiring, it is dependent on mitochondrial function and ATP generation. Loss of this energy source is the cause of rigor mortis.