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Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice.

Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Rüegg MA - EMBO Mol Med (2011)

Bottom Line: By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres.Treatment of mice with both agents results in improved muscle regeneration and increased force.Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.

View Article: PubMed Central - PubMed

Affiliation: Biozentrum, University of Basel, Switzerland. markus-a.ruegg@unibas.ch

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Related in: MedlinePlus

Contraction properties of EDL and soleus muscleEDL (A, C, E) and soleus (B, D, F) muscles from mice with the indicated genotypes.A,B. Absolute twitch force (Pt), measured by a single electrical stimulation at 15 V, is similar in dyW/dyW and dyW/Bcl mice (EDL: p = 0.52; soleus: p = 0.15) but increases from dyW/Bcl to dyW/mag (EDL: p = 0.009; soleus: p = 0.05), from dyW/mag to dyW/Bcl/mag (EDL: p = 0.018; soleus: p = 0.03) and from dyW/Bcl/mag to control (EDL: p = 0.006; soleus: p = 0.001).C,D. Maximum isometric tetanic force (P0) of EDL (C) or soleus muscle (D) expressed as percentage of controls (P0/P0 ctrl). Co-expression of Bcl2 (dyW/Bcl/mag) increases the maximal tetanic force of dyW/mag in EDL (p = 0.03) and in soleus (p = 0.02).E,F. The maximum specific tetanic force (sP0) increases gradually from dyW/dyW to control mice in both EDL (E) and soleus (F). However, no significant change of sP0 is seen between dyW/Bcl/mag and dyW/mag mice in EDL (E; p = 0.07) or in soleus (F; p = 0.24) muscle. All values represent the mean ± SEM; N numbers are shown in Table 1. p-values are Student's t-test (***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05; n.s. p > 0.05).
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fig06: Contraction properties of EDL and soleus muscleEDL (A, C, E) and soleus (B, D, F) muscles from mice with the indicated genotypes.A,B. Absolute twitch force (Pt), measured by a single electrical stimulation at 15 V, is similar in dyW/dyW and dyW/Bcl mice (EDL: p = 0.52; soleus: p = 0.15) but increases from dyW/Bcl to dyW/mag (EDL: p = 0.009; soleus: p = 0.05), from dyW/mag to dyW/Bcl/mag (EDL: p = 0.018; soleus: p = 0.03) and from dyW/Bcl/mag to control (EDL: p = 0.006; soleus: p = 0.001).C,D. Maximum isometric tetanic force (P0) of EDL (C) or soleus muscle (D) expressed as percentage of controls (P0/P0 ctrl). Co-expression of Bcl2 (dyW/Bcl/mag) increases the maximal tetanic force of dyW/mag in EDL (p = 0.03) and in soleus (p = 0.02).E,F. The maximum specific tetanic force (sP0) increases gradually from dyW/dyW to control mice in both EDL (E) and soleus (F). However, no significant change of sP0 is seen between dyW/Bcl/mag and dyW/mag mice in EDL (E; p = 0.07) or in soleus (F; p = 0.24) muscle. All values represent the mean ± SEM; N numbers are shown in Table 1. p-values are Student's t-test (***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05; n.s. p > 0.05).

Mentions: To test directly whether the difference on grip strength reflected an improvement in the force of muscles, we next measured the contractile properties in isolated extensor digitorum longus (EDL; Table 1, Fig 6A, C and E) and soleus (Table 1; Fig 6B, D and F) muscles. To avoid falsification of the results by the MDC1A-typical progressing hindleg paralysis (Miyagoe-Suzuki et al, 2000), we analysed the muscles in young, 4-week-old animals, when paralysis was not yet prominent and muscle histology of dyW/mag mice was still largely indistinguishable from control mice (Fig S4 of Supporting information). In both muscles, the wet weight, optimal contraction length (L0), CSA and the twitch-to-tetanus ratio (Pt/P0) increased from dyW/dyW, dyW/Bcl, dyW/mag and dyW/Bcl/mag to control mice (Table 1). There was some improvement in most of the parameters from dyW/dyW to dyW/Bcl mice, although this trend was never statistically significant (Table 1 and Fig 6). Interestingly, when Bcl2 and mini-agrin were co-expressed (dyW/Bcl/mag) there was a significant increase in the absolute twitch force (Pt) compared to dyW/mag mice in both EDL and soleus muscle (Table 1 and Fig 6A and B). Similarly, the normalized, maximum isometric tetanic force (Po) was higher in dyW/Bcl/mag mice than in dyW/mag mice (Fig 6C and D). However, upon normalization of Po to muscle size [i.e. maximum specific tetanic force (sPo)], the significance of the difference between dyW/mag and dyW/Bcl/mag mice got lost (Fig 6E and F). The fact that the difference between dyW/Bcl/mag and dyW/mag mice is higher for the absolute force than the specific force is in agreement with our finding (Fig 1H and E) that the number of fibres is much increased in dyW/Bcl/mag mice. Thus, although the force generated per muscle fibre is not much higher in dyW/Bcl/mag mice than in dyW/mag mice, the total force is significantly increased. These data show that expression of Bcl2 in dyW/mag mice increases muscle force by up to 50% and thus indicates that dyW/dyW mice do benefit from a combined treatment with mini-agrin and inhibition of apoptosis.


Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice.

Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Rüegg MA - EMBO Mol Med (2011)

Contraction properties of EDL and soleus muscleEDL (A, C, E) and soleus (B, D, F) muscles from mice with the indicated genotypes.A,B. Absolute twitch force (Pt), measured by a single electrical stimulation at 15 V, is similar in dyW/dyW and dyW/Bcl mice (EDL: p = 0.52; soleus: p = 0.15) but increases from dyW/Bcl to dyW/mag (EDL: p = 0.009; soleus: p = 0.05), from dyW/mag to dyW/Bcl/mag (EDL: p = 0.018; soleus: p = 0.03) and from dyW/Bcl/mag to control (EDL: p = 0.006; soleus: p = 0.001).C,D. Maximum isometric tetanic force (P0) of EDL (C) or soleus muscle (D) expressed as percentage of controls (P0/P0 ctrl). Co-expression of Bcl2 (dyW/Bcl/mag) increases the maximal tetanic force of dyW/mag in EDL (p = 0.03) and in soleus (p = 0.02).E,F. The maximum specific tetanic force (sP0) increases gradually from dyW/dyW to control mice in both EDL (E) and soleus (F). However, no significant change of sP0 is seen between dyW/Bcl/mag and dyW/mag mice in EDL (E; p = 0.07) or in soleus (F; p = 0.24) muscle. All values represent the mean ± SEM; N numbers are shown in Table 1. p-values are Student's t-test (***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05; n.s. p > 0.05).
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fig06: Contraction properties of EDL and soleus muscleEDL (A, C, E) and soleus (B, D, F) muscles from mice with the indicated genotypes.A,B. Absolute twitch force (Pt), measured by a single electrical stimulation at 15 V, is similar in dyW/dyW and dyW/Bcl mice (EDL: p = 0.52; soleus: p = 0.15) but increases from dyW/Bcl to dyW/mag (EDL: p = 0.009; soleus: p = 0.05), from dyW/mag to dyW/Bcl/mag (EDL: p = 0.018; soleus: p = 0.03) and from dyW/Bcl/mag to control (EDL: p = 0.006; soleus: p = 0.001).C,D. Maximum isometric tetanic force (P0) of EDL (C) or soleus muscle (D) expressed as percentage of controls (P0/P0 ctrl). Co-expression of Bcl2 (dyW/Bcl/mag) increases the maximal tetanic force of dyW/mag in EDL (p = 0.03) and in soleus (p = 0.02).E,F. The maximum specific tetanic force (sP0) increases gradually from dyW/dyW to control mice in both EDL (E) and soleus (F). However, no significant change of sP0 is seen between dyW/Bcl/mag and dyW/mag mice in EDL (E; p = 0.07) or in soleus (F; p = 0.24) muscle. All values represent the mean ± SEM; N numbers are shown in Table 1. p-values are Student's t-test (***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05; n.s. p > 0.05).
Mentions: To test directly whether the difference on grip strength reflected an improvement in the force of muscles, we next measured the contractile properties in isolated extensor digitorum longus (EDL; Table 1, Fig 6A, C and E) and soleus (Table 1; Fig 6B, D and F) muscles. To avoid falsification of the results by the MDC1A-typical progressing hindleg paralysis (Miyagoe-Suzuki et al, 2000), we analysed the muscles in young, 4-week-old animals, when paralysis was not yet prominent and muscle histology of dyW/mag mice was still largely indistinguishable from control mice (Fig S4 of Supporting information). In both muscles, the wet weight, optimal contraction length (L0), CSA and the twitch-to-tetanus ratio (Pt/P0) increased from dyW/dyW, dyW/Bcl, dyW/mag and dyW/Bcl/mag to control mice (Table 1). There was some improvement in most of the parameters from dyW/dyW to dyW/Bcl mice, although this trend was never statistically significant (Table 1 and Fig 6). Interestingly, when Bcl2 and mini-agrin were co-expressed (dyW/Bcl/mag) there was a significant increase in the absolute twitch force (Pt) compared to dyW/mag mice in both EDL and soleus muscle (Table 1 and Fig 6A and B). Similarly, the normalized, maximum isometric tetanic force (Po) was higher in dyW/Bcl/mag mice than in dyW/mag mice (Fig 6C and D). However, upon normalization of Po to muscle size [i.e. maximum specific tetanic force (sPo)], the significance of the difference between dyW/mag and dyW/Bcl/mag mice got lost (Fig 6E and F). The fact that the difference between dyW/Bcl/mag and dyW/mag mice is higher for the absolute force than the specific force is in agreement with our finding (Fig 1H and E) that the number of fibres is much increased in dyW/Bcl/mag mice. Thus, although the force generated per muscle fibre is not much higher in dyW/Bcl/mag mice than in dyW/mag mice, the total force is significantly increased. These data show that expression of Bcl2 in dyW/mag mice increases muscle force by up to 50% and thus indicates that dyW/dyW mice do benefit from a combined treatment with mini-agrin and inhibition of apoptosis.

Bottom Line: By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres.Treatment of mice with both agents results in improved muscle regeneration and increased force.Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.

View Article: PubMed Central - PubMed

Affiliation: Biozentrum, University of Basel, Switzerland. markus-a.ruegg@unibas.ch

Show MeSH
Related in: MedlinePlus