Recently, a single gene, DYSF, has been identified which is mutated in patients with limb-girdle muscular dystrophy type 2B (LGMD2B) and with Miyoshi myopathy (MM). This is of interest because these diseases have been considered as two distinct clinical conditions since different muscle groups are the initial targets. Dysferlin, the protein product of the gene, is a novel molecule without homology to any known mammalian protein. We have now raised a monoclonal antibody to dysferlin and report on the expression of this new protein: immunolabelling with the antibody (designated NCL-hamlet) demonstrated a polypeptide of approximately 230 kDa on western blots of skeletal muscle, with localization to the muscle fibre membrane by microscopy at both the light and electron microscopic level. A specific loss of dysferlin labelling was observed in patients with mutations in the LGMD2B/MM gene. Furthermore, patients with two different frameshifting mutations demonstrated very low levels of immunoreactive protein in a manner reminiscent of the dystrophin expressed in many Duchenne patients. Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5-6 weeks). Dysferlin is present, therefore, at a time when the limbs start to show regional differentiation. Lack of dysferlin at this critical time may contribute to the pattern of muscle involvement that develops later, with the onset of a muscular dystrophy primarily affecting proximal or distal muscles.

The summed electrical discharges generated by a contracting skeletal muscle constitute a dynamic system conveying electromyographic (EMG) information indicative of muscle physiological status. "Steady states" of activity can be achieved with light loads, but with heavy loads the dynamic system experiences continuous status transitions that culminate in task failure. The present study was designed to assess the applicability of two mathematical tools, one linear and the other nonlinear, in addressing the time course of EMG alterations under different loading challenges. Surface EMGs of the biceps brachii muscle were recorded from 14 healthy human volunteers during light and heavy loadings, and task failure occurred at varying times among the subjects. Digitized EMG signals were analyzed by linear spectral analysis (fast Fourier transform) and nonlinear recurrence-plot analysis. With light loading, computed variables from both analyses gave "quasi-steady-state" values over time, with recurrence-plot analysis having the higher variance. With heavy loading, the nonlinear variable (%determinism) increased sooner and exhibited larger changes from control values than decreases in the linear variable (spectral center frequency). Experimental results support the conclusion that both analyses can be combined to give a fuller assessment of the biceps EMG during light or heavy loading. Implications for the detection of muscular fatigue are discussed.

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