Mitochondrial respiratory chain function in skeletal muscle of ALS patients

Abstract

Evidence implicating mitochondrial dysfunction in the central nervous system of patients with sporadic amyotrophic lateral sclerosis (SALS) has recently been accumulating. In contrast, data on mitochondrial function in skeletal muscle in SALS are scarce and controversial. We investigated the in situ properties of muscle mitochondria in patients with early-stage SALS and sedentary (SED) controls using the skinned fiber technique to determine whether respiration of muscle tissue is altered in early-stage SALS in comparison with SED. Musculus vastus lateralis biopsies were obtained from 7 SED group members and 14 patients with early-stage SALS (mean disease duration, 9 months). Muscle fibers were permeabilized with saponine and then skinned and placed in an oxygraphic chamber to measure basal (V(0)) and maximal (V(max)) adenosine diphosphate-stimulated respiration rates and to assess mitochondrial regulation by adenosine diphosphate. Muscle oxidative capacity, evaluated with V(max), was identical in patients in the SALS and SED groups (V(0): SALS, 1.1 +/- 0.1; SED, 0.8 +/- 0.1, micromol 0(2). min(-1). gm(-1)dw and V(max): SALS, 3.1 +/- 0.3; SED, 2.5 +/- 0.3, micromol 0(2). min(-1). gm(-1)dw). This study shows an absence of large mitochondrial damage in skeletal muscle of patients with early-stage SALS, suggesting that mitochondrial dysfunction in the earlier stages of SALS is almost certainly not systemic.

Mitochondria in Amyotrophic Lateral Sclerosis: A Trigger and a Target

“…Similarly, a statistically signifi cant association between the occurrence of sporadic ALS and the frequency of the most common mitochondrial DNA deletion in skeletal muscle has also been reported [43] . Interestingly, such a deletion does not accumulate in ALS motor neurons or platelets [44,45] haber et al [20] are in discrepancy with more recent data showing no defect in the respiratory chain function as compared with age-and activity-matched controls [46] . Finally, a few cases of motor neuron disease reported in the literature turned out to be mitochondriopathies [47][48][49] .…”

Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis

“…Other deficits include correlations to energetics, such as decreased mitochondrial transport or a decrease in overall transport due to a drop in mitochondrial potential (Ackerley, Grierson et al 2004). Energetics: encompasses measures of all machinery and processes related to cellular respiration and production of cellular ATP (Echaniz-Laguna, Zoll et al 2002). Energetic contributors include impairments to the cellular machinery responsible for the production of ATP, especially mitochondria (Kong and Xu 1998;Sumi, Nagano et al 2006), whose dysfunction also leads to accumulation of free radicals and calcium.…”

Mechanisms of exercise limitation and pulmonary rehabilitation for patients with neuromuscular disease

“…56 In contrast, in a careful study of mitochondrial function in patients with early stage spontaneous ALS, Echaniz-Laguna et al showed no evidence of mitochondrial dysfunction. 50 Specifically, in this study, ALS individuals had similar maximal VO 2 on maximal exercise stress testing, similar muscle oxidative capacity on muscle biopsy specimens and no evidence for mitochondrial respiratory complex II or cyclooxygenase (COX) enzyme disruption compared to sedentary controls. 50 The discrepancy is likely due to the shorter mean duration of the disease (9 months) and the selective process of matching the physical activity of ALS patients to controls in the latter study.…”

“…50 Specifically, in this study, ALS individuals had similar maximal VO 2 on maximal exercise stress testing, similar muscle oxidative capacity on muscle biopsy specimens and no evidence for mitochondrial respiratory complex II or cyclooxygenase (COX) enzyme disruption compared to sedentary controls. 50 The discrepancy is likely due to the shorter mean duration of the disease (9 months) and the selective process of matching the physical activity of ALS patients to controls in the latter study. 50 For instance, mitochondrial dysfunction as assessed by lactate stress testing has been reported to be present in half of the ALS patients and to be related to the clinical severity of the disease as assessed by the Norris score.…”

“…32 There is much evidence for mitochondrial damage of the central nervous system in patients with ALS. 50 Whether this translates into mitochondrial dysfunction of skeletal muscles is unclear, and may depend on the clinical severity of the disease. For instance, in a study of 11 patients with ALS able to participate in an incremental bicycle exercise, lactate production was increased relative to controls, with an anaerobic threshold lower than that of normal subjects and non-ALS denervated controls with similar motor impairment.…”