Muscle ageing and anabolic response in the context of healthy and chronically HIV infected individuals

Abstract

In the last thirty years of the HIV epidemic, HIV has transitioned from a deadly to a chronic, manageable disease wherein infected individuals are living longer. However, despite the efficacy of antiretroviral therapy in suppressing viral burden, the quality of life is still impacted. HIV-infected individuals display symptoms associated with the elderly including a frailty related phenotype, declines in muscle and bone mass, and notably, a host response resulting in gradual increases in systemic inflammation. This physiological dysregulation leads to increased morbidity and mortality in the HIV positive population. Anabolic therapies targeting muscle loss have demonstrated the efficacy of androgen supplementation, particularly testosterone, in increasing muscle mass in both younger and older individuals, as well as in HIV positive patients. In this thesis, we drew from previous studies on aging and muscle biology to understand HIV associated decreases in muscle function. We evaluated changes in serum biomarkers between older and younger men at baseline and in response to testosterone to identify possible pathways for age related declines in muscle and testosterone response. We then evaluated genomic data from muscle biopsy tissues from HIV infected individuals, older men and younger men to identify pathways that are common to infection and aging and that may underlie declines in muscle mass and function. Finally, we characterized the identified human aging pathways in two animal models of HIV infection, the HIV transgenic rat and the SIV infected rhesus macaque. Here, we provided data on nine independent serum biomarkers related to aging and observed a subset of those that change with age to be affected by testosterone treatment. Furthermore, we found a ten gene signature in muscle that differed between young and old and showed premature expression of this signature in HIV infected people. Because the signature and biomarkers implicated TGFβ associated senescence and fibrotic pathways, we explored these pathways and phenotypes in models of HIV infection, and found suggestions of accelerated aging in muscle of HIV infected individuals. Overall, this thesis provides insights into natural aging pathways co-opted by HIV and how these pathways might play a role in declines in muscle mass and function.