Lateral transmission of force is impaired in skeletal muscles of dystrophic mice and very old rats - PubMed (original) (raw)

Lateral transmission of force is impaired in skeletal muscles of dystrophic mice and very old rats

Krishnan S Ramaswamy et al. J Physiol. 2011.

Abstract

The dystrophin–glycoprotein complex (DGC) provides an essential link from the muscle fibre cytoskeleton to the extracellular matrix. In dystrophic humans and mdx mice, mutations in the dystrophin gene disrupt the structure of the DGC causing severe damage to muscle fibres. In frog muscles, transmission of force laterally from an activated fibre to the muscle surface occurs without attenuation, but lateral transmission of force has not been demonstrated in mammalian muscles. A unique ‘yoke' apparatus was developed that attached to the epimysium of muscles midway between the tendons and enabled the measurement of lateral force. We now report that in muscles of young wild-type (WT) mice and rats, compared over a wide range of longitudinal forces, forces transmitted laterally showed little or no decrement. In contrast, for muscles of mdx mice and very old rats, forces transmitted laterally were impaired severely. Muscles of both mdx mice and very old rats showed major reductions in the expression of dystrophin. We conclude that during contractions, forces developed by skeletal muscles of young WT mice and rats are transmitted laterally from fibre to fibre through the DGC without decrement. In contrast, in muscles of dystrophic or very old animals, disruptions in DGC structure and function impair lateral transmission of force causing instability and increased susceptibility of fibres to contraction-induced injury.

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Figures

Figure 2

Figure 2. Comparison of the longitudinal and lateral transmission of forces in WT and mdx mice

Aa, a record of the maximum isometric tetanic force (_P_o) of an ATB muscle of a WT mouse. Note ATB and EDL muscles of WT and mdx mice and young and old WT rats display a very similar type of isometric force trace. Ab and c, records obtained following the attachment of the ‘yoke’ apparatus. The forces were measured during maximum stimulation of the motor nerve with the muscle at optimum length for the production of force (_L_o). Following the attachment of the ‘yoke’ apparatus, the longitudinal and lateral force traces of maximally activated WT (b) and mdx (c) muscles of mice displayed a slower initial rise in force and then a secondary even slower rise. After the attachment of the ‘yoke’, the _P_o values of the WT and mdx muscles were ∼25% lower than those of the muscles before the attachment of the ‘yoke’. Note the much closer relationship for the values for the lateral and longitudinal forces for the WT muscle than for the mdx muscle. B, relationship of longitudinal to lateral force transmission in anterior tibialis (ATB) muscles of mdx and WT mice.

Figure 1

Figure 1. The apparatus used to measure the longitudinal and lateral transmission of force

A, transmission of the force was measured from the proximal to the distal tendon to assess the longitudinal transmission of force. B, transmission of the force was measured from the proximal tendon laterally from the isometrically contracting fibres to the yoke. C, longitudinal and lateral force transmission in WT anterior tibialis anterior muscle. Note the closeness of the data to the line of identity between lateral and longitudinal force. D, diagram showing a cross-section of a skeletal muscle during the measurement of lateral transmission of forces. Note that throughout the contraction the fibres close to the surface of the muscle remain isometric between the proximal tendon and the yoke at an optimum length for force development. In contrast, the fibres toward the center of the muscle cross-section tend to shorten slightly and contribute less force than the fibres at optimum length.

Figure 3

Figure 3. Lateral and longitudinal transmission of force for EDL muscles of young, old and very old rats

Values are given as the maximum isometric tetanic forces measured from proximal to distal tendon (longitudinal force) and from the yoke to the proximal tendon (lateral force) in cases of whole muscles as well as those from decreased sets of motor units.

Figure 4

Figure 4. Expression of dystrophin–glycoprotein complex and integrin complex proteins in aged muscle membranes

One hundred micrograms of total hindlimb muscle membrane protein preparations from three young (12 month) and three very old rats (34–35 months) was analysed by SDS-PAGE and Western blotting (A) and quantified by densitometry (B) *P < 0.05 by Student's t test, data are means ±

s.e.m.

C and D, mislocalization of dysferlin and no upregulation of utrophin in aged muscle. While expression levels of dysferlin in membrane fractions is normal by Western blotting (C), immunolocalization of dysferlin (D) shows redistribution of dysferlin expression into cytoplasmic membrane compartments. E, no upregulation of utrophin was observed in aged muscle, although full length utrophin protein was detected in a positive control sample from neonatal muscle.

Figure 5

Figure 5. Increase in accumulation of interstitial connective tissue and basal lamina thickness in skeletal muscles of old rats

A, electron micrographs of three adjacent fibres of an EDL muscle showing thickening of the basal lamina in skeletal muscles of old compared to young rats. Three adjacent fibres from skeletal muscles of young (left) and old (right) rats are shown. Bar = 2 μm. B, increased abundance of fibrillar collagen and thickness of collagen IV and laminin in the basal lamina of muscle from very old rats. Picrosirius red staining followed by area analysis was used to quantify the fibrillar collagen expression in aged muscle. Immunolocalization of type IV collagen and laminin show increased thickness and staining intensity of the basal lamina. Bar = 200 μm, top two panels. Bar = 100 μm, immunofluorescence panels. Magnification of the bottom panels was increased identically for detailed comparative purposes. C, collagen composition. Two entire midbelly sections of picrosirius red stained sections from each muscle were quantified using a montage of 10× objective images, and averaged for each animal. *P < 0.005 by Student's t test, data are means ±

s.e.m.

, _n_= 3 animals in each.

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