Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe functional deficit comparable to that of DMD limb muscle, although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age), elasticity, twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age, similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings, we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.

Abstract. Through S1 nuclease mapping using a specific cDNA probe, we demonstrate that the slow myosin heavy-chain (MHC) gene, characteristic of adult soleus, is expressed in bulk hind limb muscle obtained from the 18-d rat fetus. We support these results by use of a monoclonal antibody (mAb) which is highly specific to the adult slow MHC. Immunoblots of MHC peptide maps show the same peptides, uniquely recognized by this antibody in adult soleus, are also identified in 18-d fetal limb muscle. Thus synthesis of slow myosin is an early event in skeletal myogenesis and is expressed concurrently with embryonic myosin.By immunofluorescence we demonstrate that in the 16-d fetus all primary myotubes in future fast and future slow muscles homogeneously express slow as well as embryonic myosin. Fiber heterogeneity arises owing to a developmentally regulated inhibition of slow MHC accumulation as muscles are progressively assembled from successive orders of cells. Assembly involves addition of new, superficial areas of the anterior tibial muscle (AT) and extensor digitorum longus muscle (EDL) in which primary cells initially stain weakly or are unstained with the slow mAb. In the developing AT and EDL, expression of slow myosin is unstable and is progressively restricted as these muscles specialize more and more towards the fast phenotype. Slow fibers persisting in deep portions of the adult EDL and AT are interpreted as vestiges of the original muscle primordium.A comparable inhibition of slow MHC accumulation occurs in the developing soleus but involves secondary, not primary, cells. Our results show that the fate of secondary cells is flexible and is spatially determined. By RIA we show that the relative proportions of slow MHC are fivefold greater in the soleus than in the EDL or AT at birth. After neonatal denervation, concentrations of slow MHC in the soleus rapidly decline, and we hypothesize that, in this muscle, the nerve protects and amplifies initial programs of slow MHC synthesis. Conversely, the content of slow MHC rises in the neonatally denervated EDL. This suggests that as the nerve amplifies fast MHC accumulation in the developing EDL, accumulation of slow MHC is inhibited in an antithetic fashion.Studies with phenylthiouracil-induced hypothyroidism indicate that inhibition of slow MHC accumulation in the EDL and AT is not initially under thyroid regulation. At later stages, the development of thyroid function plays a role in inhibiting slow MHC accumulation in the differentiating EDL and AT. The effects of the nerve and of thyroid hormone on these developing fast muscles therefore appear synergistic. In the adult AT and EDL, hypothyroidism causes a significant rise in proportions of slow MHC, which selectively accumulates in type Ha and not IIb fibers. This pattern of accumulation is not a simple recapitulation of early programs of slow MHC expression.

As a result of immobilization, FDI volume (as measured by computerized tomography (CT)scanning) decreased, with an accompanying reduction in aggregate EMG activity per day (P < 0.01). The force measured during MVC also decreased (P < 0.05).4. The slope of the relationship between voluntary force and MFR was significantly decreased after immobilization, as was the range of firing rate modulation (P < 0.01). Maximal MFR, estimated from the relationship between voluntary force and MFR, was decreased (P < 0.05).5. MFR was also plotted against voluntary force without being normalized with respect to MVC, and the slope of the regression line was decreased (P < 0.05). Voluntary force when the MFR was 15 Hz was estimated from regression equations for the absolute force-MFR relationship, and it was increased after immobilization (P < 0.05).6. These results suggest that firing rate modulation shows two different adaptations to joint immobilization: a restriction of motoneurone firing to the lower rates and an enhancement of the voluntary force exerted when the MFR is relatively low.

The effects of joint immobilization on the contractile properties of human skeletal muscle were examined using the first dorsal interosseous (FDI) muscle. The middle finger, index finger and thumb were immobilized for a period of 6 weeks, and the contractile properties of FDI were tested before immobilization, after 3 and 6 weeks of immobilization, and after a 6 week recovery period. Twitch and tetanic contractions of FDI were evoked by per‐cutaneous electrical stimulation. The peak twitch tension (Pt), contraction time (CT) and half‐relaxation time (1/2RT) were measured from twitch contractions, while the stimulus frequency‐force relationship was obtained from the tetanic contractions (2 s) evoked using various frequencies of stimulation (10‐100 Hz). The fatigability of FDI was tested using Burke's fatigue protocol. Pt was significantly increased after 6 weeks of immobilization (P < 0.05) but little alteration was observed in CT or 1/2RT. No change was noted in the FDI fatigue index throughout the immobilization period. The stimulus frequency‐force relationship was shifted to the left by immobilization, indicating that a larger percentage of maximal force was evoked by the lower rates of stimulation. Indeed, the tetanic force evoked by a stimulus frequency of 10 Hz was enhanced after immobilization (P < 0.05). On the other hand, the force evoked by frequencies above 50 Hz, including maximal tetanic tension, was decreased (P < 0.05). As a result, the twitch/tetanus ratio was increased (P < 0.01) after immobilization. The changes induced by immobilization in the FDI twitch/tetanus ratio and the estimated maximal firing rate of FDI motoneurones showed a significant correlation (r= 0.80, P < 0.05). It is suggested that the changes in the contractile properties of the FDI muscle seen after joint immobilization are causally linked to the changes in firing rate modulation of FDI motoneurones.

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