Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise

Abstract

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1

Correlation between exercise tolerance (V˙O2peak) and vastus lateralis O2 extraction at peak of exercise (Δ[HHb]/Δ[HHb]isch), in pALS (black line) and CTRL (broken line, not significant). White circles: pALS at baseline (T0); white squares: pALS after 4 months (T1); grey triangles: matched healthy CTRL.

Figure 2

Correlation between peak blood lactate concentration [La] and peak power at exhaustion, normalized for metabolic mass (fatty free mass, FFM), in pALS and CTRL. Four quadrants were defined by drawing dotted lines, according to one SD below the average for CTRL for both variables. White circles: pALS at baseline (T0); white squares: pALS after 4 months (T1); grey triangles: matched healthy CTRL; grey dot: pALS with vastus lateralis O2 extraction >35%. Black arrow indicates 1 patient with atypical behavior.

Figure 3

Panel (A) Correlation between V˙O2 values at exhaustion and clinical scores of ALS disease (ALSFRS-R questionnaire), recorded at baseline (T0) and after 4 months (T1). Patients with ALSFRS-R score lower than 39 (dotted line) had shorter survival time. The broken line is related only to pALS bulb. Panel (B) Correlation between V˙O2 peak and the change in ALSFRS_R score after 4 months (T1–T0). Patients with ALSFRS-R score higher than 0.65 (dotted line) had shorter survival time. Panel (C) Correlation between Mini Nutritional Assessment (MNA) questionnaire scores and ALSFRS-R at T0. Patients with 16.5 < MNA < 25 had a risk of malnutrition, while patients with MNA < 16.5 were malnourished. White circles: pALS at T0; white squares: pALS at T1; black triangles: pASL with bulbar onset (pALS bulb).

Figure 4

Relationships between V˙O2 and ventilation (V˙E) values during exercise in representative participants from the pALS (black squares) and CTRL (crosses) groups. Individually, iso-respiratory frequency (Rf) lines are indicated (pALS, continuous lines; CTRL, broken lines).

Figure 5

Correlation between orthostatic lung vital capacity (FVC) and vastus lateralis O2 extraction (Δ[HHb]/Δ[HHb]isch) at exhaustion, at baseline (T0) and after 4 months (T1), in pALS. White circles: pALS at T0; white squares: pALS at T1. Black arrow indicates 1 pALS with bulbar onset who was incapable of performing fully and correctly the spirometry maneuver.