Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney disease

Abstract

The maintenance of functional independence is the top priority of patients with chronic kidney disease (CKD). Defects in mitochondrial energetics may compromise physical performance and independence. We investigated associations of the presence and severity of kidney disease with in vivo muscle energetics and the association of muscle energetics with physical performance. We performed measures of in vivo leg and hand muscle mitochondrial capacity (ATPmax) and resting ATP turnover (ATPflux) using 31phosphorus magnetic resonance spectroscopy and oxygen uptake (O2 uptake) by optical spectroscopy in 77 people (53 participants with CKD and 24 controls). We measured physical performance using the 6-minute walk test. Participants with CKD had a median estimated glomerular filtration rate (eGFR) of 33 ml/min per 1.73 m2. Participants with CKD had a -0.19 mM/s lower leg ATPmax compared with controls but no difference in hand ATPmax. Resting O2 uptake was higher in CKD compared with controls, despite no difference in ATPflux. ATPmax correlated with eGFR and serum bicarbonate among participants with GFR <60. ATPmax of the hand and leg correlated with 6-minute walking distance. The presence and severity of CKD associate with muscle mitochondrial capacity. Dysfunction of muscle mitochondrial energetics may contribute to reduced physical performance in CKD.

Keywords: Aging; Diabetes; Mitochondria; Muscle; Nephrology.

Figure 1. Chronic kidney disease is associated with lower leg muscle ATPmax but not hand muscle ATPmax compared with controls.

Association of CKD with leg muscle mitochondrial capacity (A) and hand muscle mitochondrial capacity (B). The shaded areas represent the interquartile range (25th–75th percentile) of the data, and middle horizontal lines represent the median value for each group. P values were adjusted for age, sex, BMI, and diabetes using multivariable linear regression.

Figure 2. Kidney function is associated with in vivo leg muscle mitochondrial capacity but not hand muscle mitochondrial capacity.

Association of eGFR with leg muscle (A) and hand muscle mitochondrial capacity (B). P values were obtained using linear regression.

Figure 3. Chronic kidney disease is associated with greater resting hand muscle oxygen uptake, with no differences in resting ATPflux compared with controls.

Box plot of the association of CKD with resting hand muscle (A) O₂ uptake and (B) ATPflux. The shaded areas represent the interquartile range (25th–75th percentile) of the data, and middle horizontal lines represent the median value for each group. Hand muscle O₂ uptake was adjusted for age, sex, BMI, and ATPflux. P values were obtained using multivariable linear regression.

Figure 4. Association of serum bicarbonate level with leg muscle ATPmax among those with eGFR <60.

Serum bicarbonate levels of less than 22 mmol/L and more than or equal to 22 mmol/L from the Kidney Disease: Improving Global Outcomes recommended clinical cut point for bicarbonate repletion therapy in kidney disease. P values were adjusted for age, sex, and eGFR using multivariable linear regression.

Figure 5. Leg and hand muscle mitochondrial capacity are associated with 6-minute walk distance.

Association of leg and hand muscle ATPmax with physical performance. P for interaction by CKD status = 0.04 for leg muscle and P for interaction = 0.02 for hand muscle ATPmax using likelihood ratio test.