Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erbAalpha orphan receptor gene.

The rev-erbAalpha orphan protein belongs to the steroid nuclear receptor superfamily. No ligand has been identified for this protein, and little is known of its function in development or physiology. In this study, we focus on 1) the distribution of the rev-erbAalpha protein in adult fast- and slow-twitch skeletal muscles and muscle fibers and 2) how the rev-erbAalpha protein influences myosin heavy chain (MyHC) isoform expression in mice heterozygous (+/-) and homozygous (-/-) for a rev-erbAalpha protein null allele. In the fast-twitch extensor digitorum longus muscle, rev-erbAalpha protein expression was linked to muscle fiber type; however, MyHC isoform expression did not differ between wild-type, +/-, or -/- mice. In the slow-twitch soleus muscle, the link between rev-erbAalpha protein and MyHC isoform expression was more complex than in the extensor digitorum longus. Here, a significantly higher relative amount of the beta/slow (type I) MyHC isoform was observed in both rev-erbAalpha -/- and +/- mice vs. that shown in wild-type controls. A role for the ratio of thyroid hormone receptor proteins alpha1 to alpha2 in modulating MyHC isoform expression can be ruled out because no differences were seen in MyHC isoform expression between thyroid hormone receptor alpha2-deficient mice (heterozygous and homozygous) and wild-type mice. Therefore, our data are compatible with the rev-erbAalpha protein playing an important role in the regulation of skeletal muscle MyHC isoform expression.

Effects of aging on regulation of muscle contraction at the motor unit, muscle cell, and molecular levels.

Rodent motor units, muscle fibers, and motor proteins undergo significant aging-related changes. Such changes include spatial organization and physiological properties of fast- and slow-twitch single motor units, regulation of contractile speed and force generation capacity at the muscle fiber level, and altered functional properties of the motor protein myosin. In addition to specific changes, there also appears to be a "disorganization" of the coordinated expression of contractile, sarcoplasmic reticular, and mitochondrial protein isoforms in aging skeletal muscle. This is suggested to have a strong impact on aging-related impairments in muscle function in addition to the changes in specific muscle proteins.

Acute quadriplegic myopathy following autologous peripheral blood stem cell transplantation for breast cancer.

Autologous peripheral blood stem cell transplantation (APSCT) is increasingly used in the treatment of breast cancer. We report a patient who experienced septic shock, and after treatment with antibiotics, high-dose corticosteroids and mechanical ventilation due to respiratory insufficiency, developed quadriplegia. Electroneurophysiological examination, as well as a muscle biopsy, showed a typical picture of acute quadriplegic myopathy with loss of thick filament proteins. This is, to the best of our knowledge, the first reported case of this complication following APSCT.

Regulation of human muscle contraction at the cellular and molecular levels.

The rat is the most extensively characterized species with regard to regulation of muscle contraction and myofibrillar protein isoform expression, but there is reason to question whether results from small mammals, such as the rat, can be extrapolated directly to larger mammals, such as man. Studies of human muscle contraction have primarily used different in vivo muscle function measurements, i.e. measurements of force at different speeds of movement during electrical stimulation or voluntary activation. These measurements give important information on overall muscle function, but they are of limited value for our understanding of regulation of muscle contraction. In basic science, cellular- and molecular-physiological methods have been used for many years, but these techniques have so far only rarely been used in studies of human muscle contraction. Detailed studies of human muscle contraction can be performed in the short muscle fibre segments obtained by the percutaneous muscle biopsy technique both at the cellular and molecular level. The skinned fibre preparation in combination with a novel in vitro motility assay offers a unique possibility to investigate regulation of human muscle contraction at the cellular and molecular levels in the same muscle cell segment in both health and disease, i.e. in muscle cells characterized according to the type and amount of expressed myofibrillar protein isoforms.