Ayesha Malik
Pronouns: she/her
Research Mentor(s): Mohammed Akaaboune
Research Mentor School/College/Department: Molecular, Cellular and Developmental Bi / LSA
Program: UROPF
Session: Session 4 (1:40pm – 2:30pm)
Authors: Saad Malik, Ayesha Malik, Ahmed Bannaga, Mohammed Akaaboune
Abstract
Muscular dystrophies (MDs) are a group of muscle diseases caused by mutations in genes required for normal muscle structure and function. MDs are characterized by progressive weakness, atrophy of various voluntary muscles, and degeneration of the skeletal muscles. The severity of these diseases is associated with the extent, nature, and type of gene mutations. Most of these neuromuscular diseases result from deficiencies in the Dystrophin Glycoprotein Complex (DGC), a large multi-protein complex that links cytoskeleton actin to the extracellular matrix. The effect of DGC deficiencies on muscle and neuromuscular phenotypes was extensively studied. However, the effects of these proteins on the distribution and integrity of subcellular organelles within the cell are still less understood. In this work, we investigated the effect of the loss function of two essential components of the DGC: a-syntrophin and a-dystrobrevin on organelles organization and integrity in muscle cells. Muscles of mice deficient in a-dystrobrevin specifically intermediate muscle fiber types exhibit significant mitochondria impairment as evidenced by the high expression levels of ATP synthase, and the accumulation of abnormal mitochondria below the plasma (a hallmark of mitochondrial disorders) compared to the wild type. The abnormal mitochondrial phenotype was also observed to some extent in muscle deficient in a-syntrophin. Interestingly, in double mutant a syntrophic and a-dystrobrevin (DKO), mitochondria impairment was exacerbated. Electron microscopy of muscles deficient in either a-dystrobrevin or DKO revealed the presence of hyperbranched, abnormally shaped, and enlarged mitochondria in subsarcolemmal and intermyofibrillar spaces. Also, we found that the sarcoplasmic reticulum organization was altered and the formation of ER whorls, a type of ER stress response. Our results demonstrate that a-syntrophin and a-dystrobrevin are required for the maintenance of skeletal muscle subcellular organelles integrity.
