J Physiol. 2008 Jul 15;586(14):3337-51. Epub 2008 May 8.

Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis.

Hegedus J, Putman CT, Tyreman N, Gordon T.

Source

Centre for Neuroscience, 525 Heritage Medical Research Centre, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.

Abstract

The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast-twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1(G93A) and SOD1(WT) mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1(G93A) compared to SOD1(WT) mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1(G93A) mice (38 +/- 7) compared with SOD1(WT) controls (95 +/- 12); this was attributed to a lower proportion of the most forceful fast-fatigable (FF) MU in SOD1(G93A) mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross-sectional area (CSA) of serial sections of TA muscles stained with anti-neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1(G93A), which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity-dependent fast-to-slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast-twitch muscles of SOD1(G93A) mice involves parallel processes: (1) gradual selective motor axon die-back of the FF motor units that contain large type IIB muscle fibres, and of fatigue-intermediate motor units that innervate type IID/X muscle fibres, and (2) activity-dependent conversion of motor units to those innervated by smaller motor axons innervating type IIA fatigue-resistant muscle fibres.

PMID:: 18467368; [PubMed - indexed for MEDLINE]
PMCID:: PMC2538809

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Figure 7

The percentage of innervated muscle fibres plotted as distributions of fibre cross-sectional areas (CSAs) in the SOD1^WT (A–C) and SOD1^G93A mouse (D–E) TA muscles

In B and E, the number of each type of innervated fibre is plotted as a percentage of the total number of innervated fibres. In C and F, the number of innervated muscle fibres of each type is plotted as a percentage of the total muscle CSA (i.e. fibre area density). In A and D, mean ± s.d. of the muscle fibre CSAs are shown. In B, C, E and F, the percentage values indicate the relative proportions of type IIA, IID/X and IIB muscle fibres and the inverted triangles show the mean CSA for each muscle fibre type. A, in the SOD1^WT mouse TA muscle, the distribution of fibre CSAs was skewed towards the right, with a high proportion of muscle fibres having large CSA. B, the skewed distribution was accounted for by the differences in the proportion of the different muscle fibre types; the greatest proportion of muscle fibres was the large type IIB in the SOD1^WT mouse TA muscle. C, when the number of muscle fibres of each type is expressed as a percentage of whole muscle CSA, it becomes clear that 80% of the muscle CSA is occupied by the large type IIB muscle fibres in the SOD1^WT mouse TA muscle. D, the distribution of CSA in the SOD1^G93A mouse TA muscle was also skewed, but the range of CSA and the average CSA were both smaller than in age matched SOD1^WT mice. E, the different distribution was due to both a change in the proportion of muscle fibre types with substantially fewer type IIB fibres and a decrease in the average CSA of the type IIB muscle fibres. In addition to the decline in the average CSA of type IIB fibres, the type IIA fibres were larger, resulting in smaller differences between the mean CSA of type IIA, IID/X and IIB fibres. F, the proportions of innervated muscle fibres expressed as a percentage of the whole muscle CSA (fibre area density) was the same as the proportions of innervated muscle fibres expressed as a percentage of the total number of innervated muscle fibres.

Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis

J Physiol. J Physiol;586(Pt 14):3337-3351.

Figure 10

A possible mechanism to describe neuromuscular change in presymptomatic SOD1^G93A mouse TA muscles

A, normal; in the age-matched control SOD1^WT mouse TA muscles fibres are innervated by intact motor axons, and there is no coexpression of myosin heavy chains. B, preferential denervation; in early presymptomatic stages there is withdrawal of axon branches preferentially from the largest motor units, which innervate type IIB muscle fibres. C, activity-dependent conversion and collateral sprouting; not all of the motoneurons that innervate type IIB fibres die back, and those motor units that remain intact increase their activity to compensate for the selective and progressive loss of functional motor units. As a result of increased activity, the remaining muscle fibres change to slower, more oxidative phenotypes via coexpression of myosin heavy chains. This conversion is first evidenced by a decrease in CSA of the muscle fibres. There is also some collateral axonal sprouting from the intact motor units that innervate type IIA and IID/X muscle fibres, resulting in coexpression of muscle fibre myosin heavy chains. D, saving; collateral sprouting and activity-dependent conversion result in a progressive increase in the number of type IIA and IIX muscle fibres within motor units that become progressively enlarged by sprouting. The lower force production of the smaller muscle fibres in these surviving motor units does not compensate for the ongoing die-back and loss of the more forceful large motor units containing type IIB muscle fibres. Denervated muscle fibres that are not reinnervated become angulated and atrophy. Eventually, the proportion of type IIB muscle fibres becomes very low. As the type IIB muscle fibres produce the greatest amounts of force, the average force producing capacity of the remaining muscle fibres that are innervated by the remaining type IIA and type IIX motoneurons is reduced.

Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis

J Physiol. J Physiol;586(Pt 14):3337-3351.

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