Scalable imaging approach to measure muscle bioenergetics in CKD.

About This Grant

Project Summary/Abstract Skeletal muscle dysfunction causes frailty and disability in patients with chronic kidney disease (CKD) and contributes to their extremely high rates of mortality. A major contributor to poor muscle function in CKD is mitochondrial dysfunction; thus, the ability to identify affected patients is critical. Indeed, in vivo measurements of mitochondrial or oxidative capacity can be highly informative; they correlate with muscular endurance and may predict future loss of physical performance abilities. However, in vivo assessment of muscle oxidative capacity is typically performed using 31P magnetic resonance spectroscopy (MRS), which cannot be performed widely because of the need for dedicated expertise and hardware. We propose to use innovative technology to address this gap. We have developed a novel molecular magnetic resonance imaging (MRI)-based method that utilizes existing MRI hardware and clinical consoles in combination with innovative physics to interrogate muscle bioenergetics in a push-button manner. Our approach uses chemical exchange saturation transfer (CEST) MRI to simultaneously quantify both phosphocreatine (PCr) and creatine pools in skeletal muscle. This method, as does 31P-MRS, quantifies PCr recovery after exercise, which is the classical in vivo measure of ATP generation. Our primary objective is to quantify deficits in skeletal muscle mitochondrial bioenergetics in patients with severe CKD using CEST MRI. This proposal leverages our ongoing R01-funded prospective cohort study of patients with advanced CKD, which has assembled a patient cohort with detailed clinical, functional, and biochemical phenotyping, as well as muscle biopsies and quantitative MRI scans assessing multiple domains of skeletal muscle health. Aim 1 will determine the extent to which skeletal muscle mitochondrial bioenergetics is impaired in patients with severe, non-dialysis dependent CKD. Muscle bioenergetics will be tested pre- and post-plantar flexion exercise using CEST MRI. Aim 2 will define the independent association of muscle oxidative capacity with physical function impairment in patients with CKD after accounting for other aspects of CKD muscle pathology, which include atrophy, fibrosis, and fat infiltration. No study has simultaneously quantified each of these domains to evaluate their relative contributions to impaired physical performance; determining the added prognostic benefit of dynamic CEST- MRI in addition to static measurements requires this knowledge. This study has the additional strength of linking its findings with a wealth of data characterizing participants’ skeletal muscle health, physical performance, and kidney function. Furthermore, development of a highly scalable method to measure in vivo mitochondrial function would enable widespread testing to identify preclinical deficits, which could be a valuable early biomarker of functional decline. This would foster multicenter clinical trials, facilitate targeted exercise interventions, and drastically expand opportunities to test efficacy of mitochondrial-directed therapies.