A fundamentally important property of skeletal muscle is its ability to regenerate after damage-inducing injury. Incomplete or extended regeneration can lead to decreased skeletal muscle function and eventual muscle mass loss, which is related to an increased risk of mortality and morbidity in many disease states. Initially, skeletal muscle regeneration from injury involves the coordinated regulation of inflammation, extracellular matrix remodeling, and myofiber growth. Alterations in the temporal expression of inflammatory mediators have been shown to delay or attenuate muscle regeneration, and may be related to the processes of fibrosis and myofiber growth. Unregulated fibrosis can also inhibit myofiber regeneration. Androgens can modulate several processes related to wound repair, including the immune response and fibrosis. Immune, fibroblast, and satellite cell activity can be altered by androgen status. It is not certain if and how circulating androgen levels modulate skeletal muscle regeneration. This proposal's overall purpose is to determine if bupivacaine injection-induced mouse skeletal muscle regeneration is sensitive to circulating androgen levels, and if this sensitivity is related to altered satellite activity. The working hypothesis is that increased circulating androgens will aid in muscle regeneration by inducing satellite cell and myogenic precursor cell availability through the attenuation of several processes including: the inflammatory response, extracellular matrix remodeling related to fibrosis, and satellite cell differentiation. Additionally, the investigator hypothesizes that the androgen receptor will play a central role in regulating these regenerative processes.
Specific aim 1 will determine how differential androgen availability affects mouse skeletal muscle regeneration induced by bupivacaine injection. Experimental manipulation of androgen levels in the mouse will be performed by using either intact, castrated, or castrated plus androgen (2 dosages) treatment groups. Biochemical and morphological markers related to satellite cell activity, the muscle's inflammatory response, and extracellular matrix remodeling related to fibrosis will be examined for androgen sensitivity.
Specific aim 2 will examine the importance of the androgen receptor during skeletal muscle regeneration from bupivacaine injection. Initial experiments related to aim 2 will examine androgen receptor expression, DNA-binding activity, and protein-protein interactions during regeneration with manipulation of circulating androgen levels. The importance of androgen receptor signaling on components muscle regeneration will be examined by the administration of an androgen receptor antagonist and androgen receptor overexpression. The biochemical and morphological measurements will be similar as in aim 1.
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