Recent evidence indicates that the relative increases in muscle mass and fiber number are less in old vs. young slow-tonic anterior latissimus dorsi (ALD) muscles and twitch patagailis (PAT) muscles from Japanese quails after stretch overload (ALD=118% vs. 176%, and 24% vs. 51%, respectively; PAT=26% vs. 44%, and 9% vs. 15%, respectively). The mechanisms leading to the age-associated attenuation in muscle response are not known. It is important to know if new fibers can be formed in aging twitch muscles because a large part of the decrease in muscle strength and function in elderly humans has been attributed to age induced muscle atrophy and loss of muscle fibers. Muscle atrophy may contribute to serious health risks in the elderly and increased disability and decreased mobility. Mechanisms that might lead to increases in fiber number and size in aged muscles are not known, and it is not clear if the relative contribution of these mechanisms might differ in young and old muscle. However, the investigators' data indicate that muscle percussor cells may play an important role in new fiber formation in adult muscle, and that this may be linked with expression of one or more protooncogenes. This proposal will examine: 1) the importance of precursor cells and protooncogenes in muscle remodelling; 2) the physiological importance of stretch- induced structural adaptations in aged muscle; and 3) the importance of muscle size to motoneuron survivability in old age. Stretch-overloaded and intra-animal control PAT muscles will be examined in young adult and in very old Japanese quails after 0, 3, 5, 7, 14, 21, 30, and 60 days of stretch or after stretching from young to old age. The rate and frequency of new fiber formation will be determined by direct counting of fibers and by immunocytochemical analysis of fibers expressing non- adult myosin. The relationship between DNA synthesis in muscle precursor cells, expression of protooncogene proteins and mRNA for c-Myc, c- Fos, and c-Jun, and fiber formation, will be examined by autoradiographic, immunocytochemical, and ultrastructural techniques. Motoneuron numbers will be established after retrograde labelling of the PAT. Physiological procedures will be used to determine if the new fibers are functionally innervated and if they produce a similar force per unit area in young and old muscles. The first hypothesis is that the activation of protooncogenes and of muscles precursor cells contribute importantly to overload-induced new fiber formation and altered myosin expression. The second hypothesis is that these adaptations will improve the functional capabilities of aged muscle. A third hypothesis is that overload will induce hypertrophy that is maintained from early in life to old age, and muscle hypertrophy will increase motoneuron target size and motoneuron survivability in senescence.Examining the cellular mechanisms that contribute to new fiber formation is essential for understanding processes involved in muscle rehabilitation from disuse, wasting diseases, and age-induced muscle atrophy.
Showing the most recent 10 out of 15 publications
