# Impact of metabolic acidosis on muscle mitochondrial energetics, metabolic health and physical endurance in persons with chronic kidney disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $668,172

## Abstract

PROJECT SUMMARY AND ABSTRACT
 Chronic kidney disease (CKD) is highly prevalent affecting 14% of the U.S. population leading to
substantial morbidity and reduced quality of life. Older adults with CKD identify maintenance of functional
independence as their top priority. Skeletal muscle health is critical for mobility and an underrecognized target
of metabolic acidosis (MA) and protein energy wasting in CKD. Skeletal muscle endurance provides a window
into muscle metabolic health and muscle quality. Muscle mitochondrial metabolism is central to muscle and
walking endurance providing energy from carbohydrates and fats to power repeated muscle contraction. We
showed metabolic acidosis and muscle adiposity as the major determinants of muscle mitochondrial function.
 Metabolic acidosis (MA) is long believed to be the main mechanism leading to skeletal muscle wasting
and peripheral insulin resistance in CKD. Skeletal muscle mitochondrial metabolism is considered a principal
determinant of peripheral insulin sensitivity and muscle quality, but little is known of the impact of MA on
muscle mitochondrial function. Muscle mitochondrial dysfunction leads to defective lipid metabolism
augmenting adiposity and lipotoxic intermediates resulting in insulin resistance, low endurance, and muscle
atrophy. Using in vivo 31Phosphorus Magnetic Resonance Spectroscopy (31P MRS) we showed that the
presence and severity of CKD is strongly associated with impaired muscle mitochondrial capacity to generate
ATP translating into poor walking endurance. We also showed MA and muscle adiposity are the major
determinants of muscle mitochondrial function. Recently a non-sodium polymer (veverimer) selectively binding
hydrogen chloride in gastrointestinal tract safely improved serum bicarbonate and meaningfully improved
physical functioning in a randomized clinical trial. Despite the importance of mitochondrial function to muscle
health, it is unknown if treatment of MA benefits muscle mitochondrial function, adiposity or endurance in CKD.
 The proposed project will use precise, in vivo 31P MRS and gold-standard testing of peripheral insulin
sensitivity by hyperinsulinemic euglycemic clamp to probe the pathophysiology of MA and low endurance in a
clinical trial of alkali therapy in CKD and MA. We will compare veverimer or low-dose sodium bicarbonate to
placebo in a multicenter randomized, double-dummy placebo-controlled, cross-over trial design in 102 persons
with moderate-severe CKD and MA. First, we will test the efficacy of 3-months of alkali therapy comparing
veverimer or low dose sodium bicarbonate versus placebo on muscle metabolic health in a randomized
crossover trial in MA. Second, Test the efficacy of 3-months of alkali therapy comparing veverimer or low dose
sodium bicarbonate versus placebo on improving physical endurance in MA. Our rationale is that identification
of therapeutic targets for low physical endurance will inform the development of pharmacologic interventio...

## Key facts

- **NIH application ID:** 10278747
- **Project number:** 1R01DK129793-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Baback Roshanravan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $668,172
- **Award type:** 1
- **Project period:** 2021-08-18 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10278747

## Citation

> US National Institutes of Health, RePORTER application 10278747, Impact of metabolic acidosis on muscle mitochondrial energetics, metabolic health and physical endurance in persons with chronic kidney disease (1R01DK129793-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10278747. Licensed CC0.

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