טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentZarzhevsky Nataly
SubjectCapacity for Recovery and Molecular Mechanisms of Skeletal
Muscle Degeneration in Immobilization and Aging
DepartmentDepartment of Medicine
Supervisors Professor Abraham Reznick
Professor Raymond Coleman


Abstract

    Decreased skeletal muscle mass is a well-known phenomenon in various muscle  pathologies including disuse resulting from immobilization and also during the aging process. The molecular and cellular mechanisms involved in protein loss in skeletal muscles, are only partially  understood. We studied morphological and biochemical degenerative changes in hindlimb muscles of young (6 months old) and old (24 months old) female Wistar rats after 4 weeks immobilization of hindlimbs by external fixation and also recovery capacities 4 weeks after the external fixation device was removed and the hindlimb remobilized. An aim of the study was to try and ascertain some of the molecular and cellular events leading to induction of intracellular proteolytic systems in muscle disuse and subsequent protein degradation.


    After 4 weeks of hindlimb immobilization muscles from both young and old rats lose contractile mass and undergo marked morphological and biochemical degenerative changes. After 4 weeks remobilization the hindlimb muscles of the young rats recovered almost completely in terms of morphological and biochemical parameters, whereas the old rats had a far slower and significantly poorer recovery. The relative capacity for recovery was from 2-8 times greater in the young rats compared to the old rats.


    Subsequent studies showed evidence for oxidative stress involvement in muscle protein degradation due to hindlimb immobilization, probably through activation of Nuclear Factor-kB. An increase in the expression of inducible Nitric Oxide Synthase enzymatic activity was also found in the immobilized muscle. It was shown that these events lead to an increase in the Ubiquitin-dependent proteolytic system in skeletal muscle fibers. Similar molecular and cellular events are described in the literature for wide variety of muscle pathologies including: crush syndrome, eosinophilia-myalgia syndrome, denervation, cachexia, as well as in aging. Our study contributes to a better understanding of the molecular and cellular mechanisms associated with muscle protein degeneration and loss.