Question

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Q16 15 Points Brody myopathy is a rare genetic disorder affecting skeletal muscle. The disease is caused by an inactivating mutation in a gene that produces a protein called ATP2A1. This protein is expressed in the sarcoplasmic reticulum(SR) and helps transport calcium into the SR. Q161 5 Points Based on the role of calcium in cross-bridge cycling, does this disease cause muscle weakening or hyper-contraction? muscle weakening muscle hyper-contraction Q16.2 5 Points Why did you choose your answer in 16.1? Answer in terms of the ability of myosin to bind to actin, troponin, and tropomyosin. (Two to three sentences) Enter your answer here

Answer 1

16.1. Muscle hypercontraction occurs in Brody myopathy.

The ATP2A1 protein is responsible for transport of Ca2+ ions into the sarcoplasmic reticulum.

But, in Brody myopathy, the intracellular Ca2+ levels are high as they are not transported back to the SR.

This causes impairment in muscle relaxation and hence causing hypercontraction of muscle fibers.

16.2. The cross bridge formation occurs as follows:

• Ca2+ released from sarcoplasmic reticulum binds to troponin C.
• Calcium bound troponin C facilitates the movement of tropomyosin molecule towards the cleft of actin filament, exposing the myosin binding site of actin filament.
• This allows cross bridge formation between actin and myosin.
• ATP dependent conformational changes pulls actin filaments towards the centre resulting in sarcomere shortening.(Ratchet reaction)

When a new ATP molecule binds to myosin head, decreases the affinity of myosin for actin and thus the muscle undergoes relaxation.

If the intracellular Ca2+ is elevated, myosin undergoes another cross bridge and causes further contraction of the muscle.

The cycle continues until the SERCA pumps calcium back to the Sarcoplasmic reticulum.

Reduced intracellular Ca2+, cause detachment of troponin C and the troponin-tropomyosin complex blocks the myosin binding sites on actin.

16.3. There are no specific treatments for Brody myopathy. The treatment is mainly symptomatic, where muscle relaxants such as dantrolene are used.

Dantrolene is a skeletal muscle relaxant.

It inhibits the release of calcium from Sarcoplasmic reticulum by blocking Rynodine receptor on SR.

Blocking of Rynodine receptor reduces Ca2+ release into the myoplasm and hence the intracellular Ca2+ levels do not rise. Thus the cross bridge cycle is kept under control and the hyper contraction of muscles can be avoided.

Thus, the patient gets relief as the muscles relax.