Oxygen- and Hif1alpha-dependent regulation of skeletal muscle progenitor differentiation and skeletal muscle regeneration.

Format:

Book

Thesis/Dissertation

Author/Creator:

Majmundar, Amar J.

Contributor:

University of Pennsylvania. Cell and Molecular Biology.

Language:

English

Subjects (All):

Developmental biology.

Cytology.

Molecular biology.

Biology, Molecular.

Biology, Cell.

Health Sciences, Human Development.

0307.

0379.

0758.

Local Subjects:

Biology, Molecular.

Biology, Cell.

Health Sciences, Human Development.

0307.

0379.

0758.

Physical Description:

114 pages

Contained In:

Dissertation Abstracts International 74-03B(E).

System Details:

Mode of access: World Wide Web.

text file

Summary:

Skeletal muscle progenitors, which give rise to terminally differentiated muscle, represent potential therapies for skeletal muscle disease. These progenitors reside in a low O2 environment before local blood vessels and differentiated muscle form. It has been established that low O 2 levels (hypoxia) maintain muscle precursors in an undifferentiated state in vitro, suggesting that in developing or regenerating muscle, local hypoxia may constrain progenitor differentiation until ample nutrients are available. However, this has not been formally tested. In addition, the signals linking O2 availability with progenitor differentiation are incompletely understood. For the first part of my thesis, cell culture models were used to delineate these signals. Depleting myoblasts in vitro of the Hypoxia Inducible Factors (HIFs)—the primary effectors of O2—revealed that hypoxia regulates differentiation via HIF-dependent and -independent mechanisms. We identified a key HIF-independent mechanism—AKT inactivation—concluding that multiple O2-dependent signals regulate progenitor differentiation in vitro. As the second part of my thesis, we evaluated whether these signals regulate muscle progenitors in vivo. Mouse models were generated in which Hif1α was depleted in progenitors during development and regeneration, and revealed that Hif1α is dispensable for development but constrains regeneration. These findings are consistent with a model in which O2-dependent signals maintain the undifferentiated state of muscle progenitors.

Notes:

Source: Dissertation Abstracts International, Volume: 74-03(E), Section: B.

Adviser: M. Celeste Simon.

Thesis (Ph.D.)--University of Pennsylvania, 2011.

Local Notes:

School code: 0175.

ISBN:

9781267714176

Access Restriction:

Restricted for use by site license.