Date of Award

Spring 1-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

David L. Allen

Second Advisor

William C. Byrnes

Third Advisor

Monika R. Fleshner

Fourth Advisor

Leslie A. Leinwand

Fifth Advisor

Robert S. Mazzeo

Abstract

The basal lamina of skeletal muscle is a specialized region of extracellular matrix (ECM) comprised primarily of type IV collagen. Remodeling of the basal lamina, through altered expression or degradation of type IV collagen, is an important component of muscle plasticity. Matrix metalloproteinase-9 (MMP-9) is an inducibly expressed enzyme that degrades type IV collagen, and thus its enzymatic activity may play a key role in maintenance and plasticity of muscle structure and function. The purpose of this dissertation was to investigate the role of MMP-9-induced remodeling during normal development, exercise-induced injury, post-injury repair and aging of skeletal muscle.

Inactivation of the MMP-9 gene by homologous recombination resulted in decreases in muscle cross sectional area and enrichment of fast-twitch fiber types in several adult hindlimb muscles. Despite these compositional changes force production in MMP-9 null muscle remained normal.

Using a downhill running model of injury, I found that plasma concentration of MMP-9 in WT mice increased immediately exercise, while inactivation of the MMP-9 gene resulted in a significant decrease in post-injury muscle sarcolemmal damage. The source of MMP-9 appeared to be white blood cells and not muscle tissue itself, indicating the enzyme’s activity might be required for immune cell infiltration of damaged muscle. However, using a chemically induced model of muscle injury, I found that immune cell infiltration was not diminished in MMP-9 null mice. Similarly, MMP-9 inactivation did not impair muscle stem cell activity or muscle regeneration. Thus while MMP-9 is involved in the magnitude of the injury response it appears to be dispensable for critical aspects of the post-injury repair process.

Finally, hindlimb muscles of older WT mice had increased type IV collagen content compared to younger mice, despite the two age groups having similar levels of COL4a1 mRNA expression. Older mice also exhibited reduced MMP-2, but not MMP-9, expression in muscle, and MMP-9 inactivation did not alter collagen levels in older mice. Thus, while aging is accompanied by altered basal lamina composition MMP-9 does not appear to play a critical role in this phenomenon.

In summary, these findings demonstrate that MMP-9 is involved in most, but not all, of the remodeling events studied, with aging being the exception.

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