What is a myopathy?
Muscle disorders (also known as myopathies) in adults arise from a wide variety of hereditary and/or acquired causes. These include abnormalities in i) structural proteins (e.g. muscular dystrophies), ii) impaired muscle metabolism (e.g. disorders of carbohydrate or fat metabolism) or iii) immune-mediated inflammation (e.g. polymyositis, dermatomyositis). The primary feature of all these different abnormalities is that of muscle weakness that affects predominantly large muscle groups like the hip, thigh or shoulder muscles.
How strong a muscle can contract, or how much force it can produce, is directly related to the number of contracting muscle fibres and the contractile force generated by each of the individual fibres. As was discussed under Muscle 101, a muscle consists of various fibre types that, when activated, contributed to the total amount of force produced. Therefore, weakness may result from either a quantitative (decrease in the number of functional fibres) or qualitative (impaired muscle fibre contractility) factors.
How does a myopathy bring about muscle weakness?
Many myopathies that were passed down from the parents (hereditary), are caused by mutations in a particular gene coding for structural muscle proteins or enzymes that are essential for adequate energy production within the muscle fibres. Abnormal or dysfunctional structural proteins could theoretically lead to impaired contractility of muscle fibres, and was shown in some forms of muscular dystrophies. As the disease progresses, loss of muscle fibres most likely contributes to the weakness, and is probably the reason for the progressive nature of these disorders. The metabolic myopathies also cause weakness, with the primary factor a lack in ATP production. For example, the muscle from patients with McArdle’s disease (glycogen storage disease V), are unable to utilise its stored muscle glycogen due to a mutation in the enzyme (i.e. phosphorylase) that breaks it down to glucose units. These patients struggle to exercise and when they do, can lead to severe muscle cramps, pain, discomfort, and in some extreme cases, hospitalisation.
However, the mechanism of weakness in acquired muscle disorders is less obvious. The most frequent group of acquired muscle disorders is that of the immune and inflammatory myopathies (IIMs), consisting of polymyositis, dermatomyositis, inclusion body myositis, non-specific inflammatory myopathy and necrotising autoimmune myopathy. Weakness in this group of disorders is usually attributed to loss of muscle fibres due to inflammatory necrosis. However, it is unlikely that a decrease in the number of muscle fibres due to inflammatory necrosis is the sole mechanism responsible for weakness in IIMs, and it is probable that qualitative changes in muscle fibre contractility play an important role.
For example, the images shown above is of an athlete that was complaining of muscle cramps. By using the ATPase staining method at three pHs, it was possible to identify type II fibres that have abnormal centres (arrows). It could indicate a loss in contractile apparatus (i.e. myosin and actin) from the centre of the fibre.
Clarifying muscle weakness on a single fibre level
In vitro single muscle fibre contractility studies make it possible to directly assess the function of the cellular contractile apparatus in both healthy and diseased muscle, and are ideally suited to study muscle function at a cellular level. This technique, together with other molecular techniques, will be employed to study factors involved in muscle weakness in IIMs and McArdle’s disease. The advantage of an in vitro technique to assess contractility are two fold: i) any neurological abnormality is evaded and ii) any metabolic abnormality is side stepped.
An in-depth understanding of the mechanisms involved in the development of these disorders is of critical importance. By doing this research, we hope to gain a better understanding of the effects these disorders have on the way muscle fibres contract. Such information could potentially lead to different approaches to the treatment of these disorders.