Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy

Abstract

Objective: To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls.

Methods: Peak aerobic capacity (VO_2peak ) and workload (W_peak ) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% W_peak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near-infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X-ray absorptiometry assessed fat-free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (Fatigue_SME ) and six-minute walk test (Fatigue_6MWT ), respectively.

Results: ΔHHb-PEAK, ΔHHb-SME, VO_2peak , W_peak , FFM%, and 6MWT distance were lower (P < 0.001), and Fatigue_6MWT and Fatigue_SME were higher (P < 0.001) in SMA compared to controls. ΔHHb-PEAK correlated with FFM% (r = 0.50) and VO_2peak (r = 0.41) only in controls. Only in SMA, Fatigue_6MWT was inversely correlated with W_peak (r = -0.69), and Fatigue_SME was inversely correlated with FFM% (r = -0.55) and VO_2peak (r = -0.69).

Interpretation: This study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.

Figure 1

Muscle oxygen uptake measured as the relative change in deoxygenated hemoglobin (ΔHHb) during a CPET from rest to cool down in SMA (n = 19) and control (n = 16) participants. CPET, cardiopulmonary exercise tolerance test; SMA, spinal muscular atrophy. Light‐weight lines indicate ΔHHb for individual participants; heavy‐weight lines represent the median for SMA (green) and controls (black). Start, start of incremental exercise.

Figure 2

Muscle oxygen uptake measured as the relative change in deoxygenated hemoglobin (ΔHHb) during 10 minutes of submaximal exercise (SME) from warm‐up to cool down in SMA (n = 19) and control (n = 16) participants. Light‐weight lines indicate ΔHHb for individual participants; heavy‐weight lines represent the median for SMA (green) and controls (black). M, minute; SMA, spinal muscular atrophy.

Figure 3

(A and B) Fatigue represented as percent change in (A) distance walked from 1st minute to the 6th minute of the 6MWT and (B) workload from the 1st minute to the 10th minute of submaximal cycle exercise in SMA participants (n = 19) and healthy controls (n = 16). 6MWT, six‐minute walk test; SME, submaximal exercise; SMA, spinal muscular atrophy. *P < 0.001.