Letter to the Editor |
Mitochondrial changes in skeletal muscle in amyotrophic lateral sclerosis and other neurogenic atrophies—a comment
Departments of 1 Epileptology and 2 Neurology, University of Bonn, Bonn and 3 Department of Neurology II, University of Magdeburg, Magdeburg, Germany
Correspondence to: Wolfram S. Kunz, PhD, University of Bonn, Department of Epileptology, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany E-mail: wolfram.kunz{at}ukb.uni-bonn.de
Received July 15, 2005. Accepted September 9, 2005.
Sir,
We read with great interest the article by Krasnianski et al. (2005)
recently published in your journal. The authors report the absence of specific alterations of respiratory chain activities in skeletal muscle of patients with amyotrophic lateral sclerosis (ALS) and neurogenic atrophies (NA). While the data concerning NA patients are completely in line with our previous observations on six patients with spinal muscular atrophy and two patients with Tay–Sachs syndrome (cf. Vielhaber et al., 1999), a considerable discrepancy exists between this report and data on ALS biopsies reported by our group (cf. Wiedemann et al., 1998; Vielhaber et al., 1999, 2000, 2001, 2003). To explain the contradictory findings, we would like to comment on differences in the investigated patient population and on the applied methods:
- The ALS patients included in the study by Krasnianski et al. (2005) had a mean disease duration of 18 months (range 12–48), while a recent patient group reported by us had a mean disease duration of 10 months (range 6–18) (Vielhaber et al., 2003). The influence of the disease duration on mitochondrial enzyme activities in skeletal muscle of 22 patients with definite (n = 16) or probable (n = 6) sporadic ALS (SALS, definition according to the El Escorial Criteria, World Federation of Neurology, 1994) is shown in Table 1. We saw a clear decline of citrate synthase normalized activities of complex I and complex IV in 12 short disease duration SALS patients, which is in contrast to the results on 8 not further characterized ALS patients presented by Krasnianski et al. (2005). In detail, we observed a significant tendency to normalization of citrate synthase normalized complex IV activity with increasing disease duration comparing two disease subgroups (SALS I, mean disease duration from first reported symptoms to muscle biopsy 11.2 months, range 6–16, mean age 55 years, range 30–67; SALS II, mean disease duration 28.4 months, range 21–40, mean age 59 years, range 50–71). The clinical examination revealed a significant difference in the ALSFRS-R score (Cedarbaum et al., 1999) between both disease subgroups: SALS I 39 (range 36–44) versus SALS II 29 (range 17–39; P = 0.02). This finding supports the specificity of mitochondrial dysfunction in SALS skeletal muscle and points against an artefact caused by chronic denervation. Respiratory chain enzyme deficiencies in the SALS I group are quantitatively comparable with muscle biopsy data from patients harbouring the A3243G tRNALeu(UUR) mitochondrial DNA point mutation. The lack of specific effects on respiratory chain enzyme activities as well as the considerable decrease of non-collagen protein in the biopsies of the ALS group reported by Krasnianski et al. (2005) could therefore be explained by long disease duration.
- Krasnianski et al. (2005) presented data from biceps brachii, deltoid, anterior tibialis and vastus lateralis muscles, while we examined mainly vastus lateralis and rarely deltoid muscles (Vielhaber et al., 2000, 2003). The heterogeneity of the examined skeletal muscle specimen might introduce some additional scatter of the results in the 8 ALS patients reported by Krasnianski et al. (2005).
- The results on mtDNA/nDNA ratios in 24 ALS patients reported by Krasnianski et al. (2005) were obtained by densitometry of X-ray films from chemiluminescence-developed Southern blots. This method suffers from linearity problems and certainly does not allow a reliable quantification of individual DNA signals (cf. Sambrook et al., 1989). Moreover, it has to be mentioned that in the blot presented in Figure 2, both bands are 11.5 kb apart, and the band intensity ratios are 5—unfavourable conditions to detect small deviations of mtDNA/nDNA ratios. In contrast, we used the quantitative detection of [32P]labelled probes with a phosphoimager—a method known for its excellent linearity and reliability (Vielhaber et al., 2000).
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In conclusion, we think that the apparent discrepancies between the results of Krasnianski et al. (2005)
and our previous work are mainly related to differences in patient population and applied methods. Available experimental data from other groups also support mitochondrial dysfunction in SALS (Comi et al., 1998; Borthwick et al., 1999; Dupuis et al., 2003). In this context, we further refer to the broad experimental evidence of early mitochondrial dysfunction occurring in different tissues from transgenic mice expressing a mutant form of the gene encoding Cu/Zn superoxide dismutase (SOD-1) that is associated with familial cases of ALS (Kong and Xu, 1998; Mattiazzi et al., 2002). References
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  A. Krasnianski, M. Deschauer, M. Krasnianski, and S. Zierz Reply to 'Mitochondrial changes in skeletal muscle in amyotrophic lateral sclerosis and other neurogenic atrophies--a comment'. Brain, March 1, 2006; 129(Pt 3): E41 - E41. [Full Text] [PDF]
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