PROJECT SUMMARY / ABSTRACT The age-related loss of muscle mass, strength, and function, known as sarcopenia, represents one of the most common conditions in older adults. Of these conditions, sarcopenia is the only one for which no FDA-approved treatment exists. To promote independence and prevent disability in our aging population, the identification of drug targets for sarcopenia is crucial. Type 2 Diabetes Mellitus (T2DM) is an ideal model for this purpose because sarcopenia is accelerated in older people who have T2DM. It may be possible to identify new drug targets for the accelerated sarcopenia of T2DM by contrasting pathway dysregulation in healthy older controls and in patients with T2DM. One promising potential target, upregulated by the hyperglycemic milieu of T2DM, is non-enzymatic protein glycosylation (known as glycation) and the subsequent formation of advanced glycation end-products (AGE). This detrimental process is known to contribute to multiple conditions, including T2DM, Alzheimer’s disease, and low-grade inflammation. Increased AGE concentration has previously been linked to decreased muscle strength and function in cross-sectional studies. Furthermore, blocking AGE accumulation in animal models improves muscle mass. However, the role of AGE in sarcopenia in humans has yet to be substantiated. We propose that AGE represents a potential mediator of accelerated sarcopenia in humans with T2DM. However, more preliminary evidence of muscle AGE responsiveness to existing treatment modalities – such as resistance exercise – is needed to design specific clinical trials. The proposed ancillary study to parent R01 AG049611 will examine AGE in older subjects with T2DM and healthy controls before and after 12 weeks of progressive resistance exercise training. We hypothesize that progressive resistance exercise training will reduce AGE concentrations in plasma and muscle, and that these reductions will be associated with improved sarcopenia outcomes – namely, muscle mass, strength, and function. We will also test the hypothesis that progressive resistance exercise training can improve protein glycation and AGE accumulation in T2DM older patients to levels not different from that of healthy older controls. By employing clinical, proteomic, and biochemical methodologies, the present study will address this hypothesis through three Specific Aims: 1) identify and quantify glycated protein targets in the skeletal muscle and plasma from older adults with and without T2DM, 2) identify the effects of progressive resistance exercise training on AGE concentration and downstream effectors of AGE, and 3) determine whether AGE concentration is associated with baseline differences or intervention-induced changes in measures of muscle mass, strength, or function, and estimate how much of the variation in these measures is explained by AGE concentration. Determining the impact of progressive resistance exercise training on AGE accumulation will inform th...