A 17-year-old boy is referred to a clinic for ongoing muscle weakness. He has noticed difficulty climbing stairs at home over the last several months, and he recently stopped playing basketball due to difficulty lifting the ball over his head. The patient takes no medications and does not know of any family members with muscle weakness. On neurologic examination, he is unable to lift his arms or legs against resistance when fully outstretched. He undergoes a muscle biopsy to evaluate the cause of his proximal muscle weakness. Electron microscopy of the specimen reveals sparse transverse tubules in some of the muscle fibers. Which of the following is the most likely consequence of this patient's biopsy findings?
Show Explanatory Sources
Transverse tubules (T-tubules) are invaginations of the muscle cell membrane (sarcolemma) located in close proximity to the terminal cisterns of the sarcoplasmic reticulum. They are found in striated (eg, cardiac, skeletal) muscle and contain voltage-gated L-type calcium channels (dihydropyridine receptors) adjacent to the ryanodine receptors on the terminal cisterns. During muscle contraction, T-tubules allow the depolarization impulse to rapidly propagate through the interior of the muscle fiber. This ensures that calcium release from the sarcoplasmic reticulum occurs uniformly throughout the fiber, allowing for synchronized contraction of myofibrils in each muscle cell.
This patient most likely has a form of limb girdle muscular dystrophy due to a mutated sarcolemma protein (eg, caveolin) affecting excitation-contraction coupling. Decreased numbers of functional T-tubules in affected muscle fibers lead to uncoordinated contraction of myofibrils, which manifests as muscle weakness.
(Choice A) Decremental force generated on repeated stimulation characterizes myasthenia gravis, an autoantibody disorder inhibiting postsynaptic acetylcholine receptors in the neuromuscular junction. A constant low response to repeated nerve stimulation is more likely if T-tubules are lacking.
(Choice B) ATP fuels myosin movement along actin filaments (causing contraction) and drives the pumps that transport calcium back into the sarcoplasmic reticulum (causing relaxation). McArdle disease is one cause of impaired ATP production and occurs due to a failure of muscle glycogen breakdown.
(Choice C) Impaired relaxation after sustained contraction occurs in myotonic dystrophy due to a trinucleotide repeat expansion altering myotonin-protein kinase. This protein facilitates myosin head detachment from the actin filament to enable muscle relaxation; T-tubules do not play a role.
(Choice D) A mutation in troponin C may block its response to intracellular calcium and prevent muscle contraction. However, muscle fibers with decreased numbers of T-tubules will maintain limited contractility.
Educational objective:
Transverse tubules (T-tubules) are invaginations of the sarcolemma that transmit depolarization signals to the sarcoplasmic reticulum to trigger the release of calcium and induce muscle contraction. The uniform distribution of T-tubules in striated muscle fibers ensures that each myofibril contracts at the same time, which is necessary for efficient contraction.