Grant Duration
07/19 – 08/23
Dysferlin is 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 (also known as ryanodine receptors) 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 the calcium release channels in the muscle. Work in Prof Robert Bloch’s lab has shown that the calcium release channels in dysferlinopathy can become “leaky” to calcium following stressful contractions in mildly dystrophic muscles. We assessed the calcium release channel leakiness in the absence of stressful contractions and the subsequent redistribution of calcium within the muscle fibres of dysferlin-deficient muscles that displayed either a mild or strongly dystrophic condition; and also the corresponding muscles in healthy mice. We found that the calcium release channel is leaky in muscle that eventually displays a strongly dystrophic condition before the muscle displays pathology; and the leak increases significantly with age. In contrast, muscles that only show mild dystrophy do not display excessive calcium leak at either a young or older age. The exacerbation of the leak in strongly dystrophic muscles was dependent on the combination of the absence of dysferlin and differences that exist between these muscles in the body (differences that have their origin in the healthy mouse). In association with increased leak, we found proportional depletion of calcium from the sarcoplasmic reticulum and loading of calcium into the mitochondria in muscles, which will affect muscle contractility, metabolism and cause increasing oxidation with time. Our results may indicate that changes in calcium release channel leak are a triggering event for the progression of dysferlinopathy.
