Ca2+ handling and tubular (t-) system function in dysferlinopathy
Dysferlin is located in the specialized plasma membrane of the skeletal muscle fibre. The outer, plasma membrane of muscle fibres invaginates into the fibre at regular intervals to reach the location where calcium release channels exist that are critical to controlling muscle contraction in response to stimulation by nerve impulses. The invagination of the plasma membrane is known as known as t-tubules, or collectively known as the t-system, directly meets all of the calcium release channels in the muscle. Recent work in Prof Robert Bloch’s lab (support by Jain Foundation) has shown that the calcium release channels in dysferlinopathy can become “leaky” to calcium following stressful contractions. The calcium release channel become leaky in the times when the muscle is at rest (not needed for contractions). The ensuing increases in calcium levels inside the resting muscle can be deleterious and could underlie the pathology observed in this condition. Little is known about how calcium levels are controlled in the healthy resting muscle or how this may change in dysferlinopathy. My lab has recently developed sensitive techniques that allow us to detect the tiny movements of calcium from the calcium release channel by placing calcium sensors in the t-tubules. We will study how calcium handling of the resting muscle changes in responses to stress and age in dysferlinopathy to increases our knowledge of the progression of dysferlinopathy and to identify targets for therapeutic intervention in dysferlinopathy.