Human immunodeficiency virus (HIV) associated weight loss and muscle wasting remain significant clinical concerns even in the era of potent antiretroviral therapy. The pathogenic sequelae leading to HIV-associated muscle wasting are multi-factorial but can often be characterized by inflammatory muscle degeneration. While androgen supplementation increases muscle mass in treated subjects, significant side effects limit their long-term use. Therefore, there is a need to identify additional mechanisms that promote muscle regeneration. Muscle tissue contains resident muscle precursor cells (MFCs) that are critical in the myogenic regeneration capacity of muscle tissue in response to disuse, damage or atrophy. Notably, in addition to displaying responsiveness to growth promoting androgens, MFCs also release monocyte chemoattractants and require the presence of recruited monocytes / macrophages to repair damaged muscle in animal models. Paradoxically, stimulated macrophages can be pro-inflammatory, raising the possibility for a phenotype that contributes to muscle wasting, rather than promoting muscle growth. HIV infection may tip this balance. The overall objective of this proposal is to characterize the interplay between distinct modes of macrophage stimulation with MFC commitment and differentiation to better understand the conditions that facilitate myogenesis. We hypothesize that HIV infection may favor the emergence of a """"""""classical"""""""" pro-inflammatory phenotype, rather than an """"""""alternative"""""""" anti-inflammatory phenotype, thereby exacerbating muscle loss. We propose to evaluate the role of macrophage soluble mediators and HIV infection in myogenesis at the immunohistochemical (Aim 1), genomic / proteomic (Aim 2) and chromatin biochemistry (Aim 3) levels to precisely define the muscle genetic program and to distinguish muscle lineage commitment with atrophy signaling. To insure the success of this proposal, we have assembled a multidisciplinary team with expertise in endocrinology, muscle biology, molecular virology and genomics to study macrophage-muscle precursor cell interaction in the context of HIV infection.
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