Novel mechanisms of muscle and bone loss with HIV infection, antiretroviral therapy, and aging.

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Our proposal is in direct response to the special Funding Opportunity Announcement (FOA) PAR-21-068 “Multidisciplinary Studies of HIV/AIDS and Aging (R01)”. A frailty phenotype is frequently observed in HIV patients on long term antiretroviral therapy (ART), and both osteoporosis and sarcopenia are now recognized as co-morbidities among older people with HIV. Loss of muscle mass and strength are in turn associated with poor health outcomes ranging from falls and fractures to accelerated disease progression and increased mortality. Our goal is to address this problem by providing critical, new information on the cellular and molecular mechanisms underlying musculoskeletal dysfunction with HIV infection and ART, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Recent studies identify the aryl hydrocarbon receptor (AhR) as playing a key role in regulating organismal aging and lifespan. Our group has found that AhR activation can induce senescence in bone marrow stem cells, and others have observed that AhR overexpression induces muscle atrophy. Uniting these observations, our central hypothesis is that muscle- and bone-specific AhR activation are key drivers of muscle and bone loss in patients with HIV on ART. Our preliminary data provide a strong rationale for this hypothesis and indicate that 1) markers of muscle atrophy, bone loss, and AhR activation are increased in our mouse model of HIV infection, 2) AhR is highly expressed in muscle and bone, and targeted knockout of AhR in these tissues increases lean mass and trabecular bone mass, 3) pharmacological inhibition of AhR increases muscle strength and markers of bone formation in mice, and 4) the antiretroviral emtricitabine (FTC) increases AhR activation and senescence in muscle cells and these effects are attenuated by AhR silencing. Specific Aim 1 tests the hypothesis that AhR activation is a key factor driving muscle and bone loss with aging and HIV infection. Specific Aim 2 tests the hypothesis that AhR activation is a key factor driving muscle and bone loss with aging and antiretroviral therapy. Our expected outcomes include 1) defining the role of AhR in skeletal muscle and bone with HIV infection and ART so that it can be targeted therapeutically, and 2) characterizing the impact of aging and ART on AhR activation in skeletal muscle and bone. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of HIV- and age-induced pathologies. Ultimately, these data will enable clinicians to improve disease outcomes and, consequently, public health.