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Regulation of the Structure and Function of Skeletal Muscle and Tendon by Myostatin.

dc.contributor.authorMendias, Christopher L.en_US
dc.date.accessioned2008-01-16T15:16:33Z
dc.date.available2008-01-16T15:16:33Z
dc.date.issued2007en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/57707
dc.description.abstractThe ability of skeletal muscle and tendon to adapt to use and disuse has important consequences for determining the health, mobility and athletic performance of an individual. Muscle generates the forces for locomotion, and tendons link muscle to bone and can protect muscle fibers from contraction-induced injuries. Myostatin (GDF-8) is a member of the TGF-beta superfamily of cytokines. Inhibition of myostatin leads to a profound increase in muscle mass, and consequently there is much interest in the potential of myostatin inhibitors to treat injuries and diseases that lead to muscle atrophy. Using whole muscle and tendon mechanics experiments in the myostatin-deficient mouse model, along with cellular and molecular studies, we determined the impact of myostatin deficiency on the structure and function of skeletal muscle and tendon tissue. The deficiency of myostatin lead to muscle fiber hypertrophy and hyperplasia. Myostatin-deficient EDL muscles have a decrease in protein degradation due to a decrease in atrogin-1 expression. Myostatin deficiency decreased the type I collagen content of EDL muscles. The deficiency of myostatin increased the maximum isometric force of both EDL and soleus muscles, but decreased the specific force of EDL muscles. Furthermore, EDL muscles of myostatin-deficient mice are more susceptible to contraction-induced injury. Therefore, we determined if myostatin regulates the structure and function of tendons. Transcripts for myostatin and the myostatin receptors, ACVR2B and ACVRB, are present in tendons. Surprisingly, the tendons of myostatin-deficient mice are smaller, have a decrease in fibroblast density and type I collagen. Myostatin-deficient tendons also have a decrease in the expression of two genes that promote tendon fibroblast proliferation, scleraxis and tenomodulin. Treatment of tendon fibroblasts with myostatin activates the p38MAPK and Smad2/3 signaling cascades, increases cell proliferation and the expression of type I collagen, scleraxis and tenomodulin. Tendons from myostatin-deficient mice have a greater peak stress, lower peak strain and an increase in stiffness. We conclude that myostatin has a profound impact on the structure and function of skeletal muscle and tendon tissue. The partial inhibition of myostatin is likely to be beneficial in the treatment of many types of muscle injuries and diseases.en_US
dc.format.extent1373 bytes
dc.format.extent3471029 bytes
dc.format.mimetypetext/plain
dc.format.mimetypeapplication/pdf
dc.language.isoen_USen_US
dc.subjectMyostatinen_US
dc.subjectMuscle Mechanicsen_US
dc.subjectTendon Mechanicsen_US
dc.titleRegulation of the Structure and Function of Skeletal Muscle and Tendon by Myostatin.en_US
dc.typeThesisen_US
dc.description.thesisdegreenamePh.D.en_US
dc.description.thesisdegreedisciplineMolecular and Integrative Physiologyen_US
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studiesen_US
dc.contributor.committeememberFaulkner, John A.en_US
dc.contributor.committeememberHerzog, Susan Brooksen_US
dc.contributor.committeememberHorowitz, Jeffrey F.en_US
dc.contributor.committeememberMichele, Daniel E.en_US
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biologyen_US
dc.subject.hlbsecondlevelPhysiologyen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/57707/2/cmendias_1.pdfen_US
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


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