People living with HIV infection (PLWH) are living longer but experience accelerated functional decline, which can be manifested as increased exercise-associated fatigue and dyspnea as compared to non-infected individuals. Functional decline is associated with impaired quality of life, increased vulnerability to superimposed stresses, and the likelihood of premature morbidity and mortality. The responsible mechanisms, however, are poorly understood. Considerable pre-clinical data and our pilot clinical studies using 31P magnetic resonance spectroscopy (MRS) suggest an “energetic myopathy” as a possible basis for the fatigue and decreased performance in older PLWH individuals. In addition, inflammation impairs mitochondrial function and is increased with advanced age per se, as well as in combined ART treated and viral-suppressed PLWH. Altered cardiac metabolism and performance may also contribute to exercise intolerance and this study proposes examination of cardiac high energy phosphate metabolism, its causes and the consequences for left ventricular diastolic dysfunction (DD) in PLWH. The central hypothesis of this study is that impaired cardiac mitochondrial energy metabolism contributes to diastolic dysfunction and to exercise intolerance in PLWH. The specific aims are 1) to define the scope and extent of myocardial energetic abnormalities at rest and exercise using 31P MRS/MRI in PLWH, 2) to probe the factors underlying cardiac muscle mitochondrial and energetic abnormalities in PLWH, including factors unique to PLWH (ART history and cumulative viral history) and others more common in PLWH (increased inflammation, immune activation, insulin resistance, and/or higher cardiac muscle lipids by MRI), and 3) to determine the functional significance of observed cardiac muscle energetic changes in PLWH for DD and, in turn, for EI. The studies will leverage expertise, resources, and established PLWH cohorts at Johns Hopkins and collect novel cardiac energetic, diastolic function, quantitative exercise tolerance and biomarker data. This proposal will deliver novel understanding of the type and extent of myocardial energetic-mitochondrial abnormalities in PLWH, the factors prevalent in PLWH that are most closely related to such cardiac mitochondrial-energetic changes, and the functional impact on diastolic dysfunction and, in turn, exercise intolerance. These studies, characterizing the presence and functional consequences of what appears to be a “mitochondriopathy” of cardiac and skeletal muscle of PLWH promise new avenues to better understand the problem and to design metabolic strategies to reduce the personal and societal impact of HIV disease-related functional decline in this important and growing population.