Strength and aerobic training attenuate muscle wasting and improve resistance to the development of disability with aging.

By the age of 50 yrs old, humans become aware that they are losing muscle strength (mass) and endurance (mitochondria). A frequent symptom of neuromuscular disorders is muscle weakness (Walton, 1988). We define the aging-associated muscle wasting as a progressive neuromuscular syndrome that will lower the quality of life in the elderly by (1) decreasing the ability to lift loads (progressing to difficulty arising from a chair), and (2) decreasing endurance (leading to an inability to perform the activities of daily living, which increases health care costs). Campion (1994) states that the most successful outcome would be for the very elderly to take control of the last stage of their life and make it worth living. To obtain this goal, prevention of muscle wasting is an absolute requirement. Muscle mass and motor unit number, activation, and synchronization are highly related to strength; both decrease with aging (Rodgers and Evans, 1993). Resistance-training is the best way to increase muscle mass, neural coordination, and strength. Mitochondrial concentration is highly related to endurance capacity in young and old (Holloszy and Coyle, 1984). Both muscle contractile and mitochondrial protein decrease with aging in sedentary humans (reviewed by Rodgers and Evans, 1993). Endurance training, which is the best exercise to increase/maintain mitochondrial concentration with aging, has generally resulted in relatively small functional benefits to nursing home patients (Fiatarone et al., 1994).(ABSTRACT TRUNCATED AT 250 WORDS)

Regenerated mdx mouse skeletal muscle shows differential mRNA expression.

Despite over 3,000 articles published on dystrophin in the last 15 years, the reasons underlying the progression of the human disease, differential muscle involvement, and disparate phenotypes in different species are not understood. The present experiment employed a screen of 12,488 mRNAs in 16-wk-old mouse mdx muscle at a time when the skeletal muscle is avoiding severe dystrophic pathophysiology, despite the absence of a functional dystrophin protein. A number of transcripts whose levels differed between the mdx and human Duchenne muscular dystrophy were noted. A fourfold decrease in myostatin mRNA in the mdx muscle was noted. Differential upregulation of actin-related protein 2/3 (subunit 4), beta-thymosin, calponin, mast cell chymase, and guanidinoacetate methyltransferase mRNA in the more benign mdx was also observed. Transcripts for oxidative and glycolytic enzymes in mdx muscle were not downregulated. These discrepancies could provide candidates for salvage pathways that maintain skeletal muscle integrity in the absence of a functional dystrophin protein in mdx skeletal muscle.

Effect of aging on human skeletal muscle and motor function.

The percentage of Americans over the age of 65 yr is growing and this trend has heightened interest in aging research. In this review of human studies, comparisons, as a function of age, are made among the declines of VO2max, work endurance, muscle strength, total muscle cross-sectional area, muscle fiber number, spinal motor neuron number, and motor unit number. Declines in VO2max and total cross-sectional area of leg muscle begin in early adulthood. However, an accelerated loss of total muscle area and a decrease in muscle fiber number begins at about 50 yr of age. Losses in spinal motor neurons and motor units become apparent at about 60 yr of age. However, these findings were collected on different subjects. By better defining these temporal relationships in the same subjects, a more accurate cause and effect relationship may be obtained. Although muscle atrophy is attenuated by resistance training with aging, little is known about the effects of resistance training on the loss of spinal motor neurons, motor units, and muscle fiber number. The goal of this research would be to enhance the ability to promote as much function and independence of living as possible, i.e., increase the quality of life in our expanding elderly population.

Olympic goal: molecular and cellular approaches to understanding muscle adaptation.

Skeletal muscle is a plastic tissue showing adaptations to training that permit more physical work with less fatigue. Delineation of basic mechanisms of these adaptations will allow the development of scientifically based programs of exercise as well as potential new drugs for the maintenance of physical fitness.

Cytoplasm-to-myonucleus ratios and succinate dehydrogenase activities in adult rat slow and fast muscle fibers.

The relationship between myonuclear number, cellular size, succinate dehydrogenase activity, and myosin type was examined in single fiber segments (n = 54; 9 +/- 3 mm long) mechanically dissected from soleus and plantaris muscles of adult rats. One end of each fiber segment was stained for DNA before quantitative photometric analysis of succinate dehydrogenase activity; the other end was double immunolabeled with fast and slow myosin heavy chain monoclonal antibodies. Mean +/- S.D. cytoplasmic volume/myonucleus ratio was higher in fast and slow plantaris fibers (112 +/- 69 vs. 34 +/- 21 x 10(3) microns3) than fast and slow soleus fibers (40 +/- 20 vs. 30 +/- 14 x 10(3) microns3), respectively. Slow fibers always had small volumes/myonucleus, regardless of fiber diameter, succinate dehydrogenase activity, or muscle of origin. In contrast, smaller diameter (< 70 microns) fast soleus and plantaris fibers with high succinate dehydrogenase activity appeared to have low volumes/myonucleus while larger diameter (> 70 microns) fast fibers with low succinate dehydrogenase activity always had large volume/myonucleus. Slow soleus fibers had significantly greater numbers of myonuclei/mm than did either fast soleus or fast plantaris fibers (116 +/- 51 vs. 55 +/- 22 and 44 +/- 23), respectively. These data suggest that the myonuclear domain is more limited in slow than fast fibers and in the fibers with a high, compared to a low, oxidative metabolic capability.

Molecular and cellular adaptation of muscle in response to physical training.

Molecular biology tools can be used to answer questions as to how adaptations occur in skeletal muscle with training that could provide new frameworks to improve physical performance. A number of mRNAs for transfer of metabolic substrates into muscle cells increase after a single bout of exercise demonstrating the responsiveness of some gene expression to exercise. In stretch-induced hypertrophy SRE1 of the skeletal alpha-actin promoter is required to transactivate the promoter. Less retardation of SRF in crude nuclear extracts from the stretched muscle implies a conformational change in SRF because of the stretch. Transgenic animals will provide a tool to test questions concerned with how exercise signals adaptive changes in gene expression. Molecular biological approaches will be able to evaluate the interaction between physical activity levels and the expression of genes that modulate the susceptibility to many chronic diseases. Benefits of exercise extend beyond fitness to better health. Molecular biology is an important tool which should lead to improved physical performance and health in both elite athletes and the general public.

Activation of the myogenin promoter during mouse embryogenesis in the absence of positive autoregulation.

Myogenin, a member of the MyoD family of helix-loop-helix proteins, can induce myogenesis in a wide range of cell types. In addition to activating muscle structural genes, members of the MyoD family can autoactivate their own and cross-activate one another's expression in transfected cells. This has led to the hypothesis that autoregulatory loops among these factors provide a mechanism for amplifying and maintaining the muscle-specific gene expression program in vivo. Here, we make use of myogenin-null mice to directly test this hypothesis. To investigate whether the myogenin protein autoregulates the myogenin gene during embryogenesis, we introduced a myogenin-lacZ transgene into mice harboring a null mutation at the myogenin locus. Despite a severe deficiency of skeletal muscle in myogenin-null neonates, the myogenin-lacZ transgene was expressed normally in myogenic cells throughout embryogenesis. These results show that myogenin is not required for regulation of the myogenin gene and argue against the existence of a myogenin autoregulatory loop in the embryo.

Human bHLH transcription factor gene myogenin (MYOG): genomic sequence and negative mutation analysis in patients with severe congenital myopathies.

The myogenin gene encodes an evolutionarily conserved basic helix-loop-helix transcription (bHLH) factor that is required for differentiation of skeletal muscle, and its homozygous deletion in mice results in perinatal death from respiratory failure due to the lack of muscle fibers. Since the histology of skeletal muscle in myogenin null mice is reminiscent of that found in severe congenital myopathy patients, many of whom also die of respiratory complications, we sought to test the hypothesis that an aberrant human myogenin (myf4) coding region could be associated with some congenital myopathy conditions. With PCR amplification, we found similarly sized PCR products for the three exons of the myogenin gene in DNA from 37 patient and 40 control individuals. In contrast to previously reported sequencing of human myogenin (myf4), we describe with automated sequencing several base differences in flanking and coding regions plus an additional 659 and 498 bp in the first and second introns, respectively, in all 37 patient and 40 control samples. We also find a variable length (CA)-dinucleotide repeat in the second intron, which may have utility as a marker for future linkage studies. In summary, no causative mutations were detected in the myogenin coding locus of genomic DNA from 37 patients with severe congenital myopathy.

Pulmonary hypoplasia in the myogenin null mouse embryo.

Although fetal breathing movements are required for normal lung development, there is uncertainty concerning the specific effect of absent fetal breathing movements on pulmonary cell maturation. We set out to evaluate pulmonary development in a genetically defined mouse model, the myogenin null mouse, in which there is a lack of normal skeletal muscle fibers and thus skeletal muscle movements are absent in utero. Significant decreases were observed in lung:body weight ratio and lung total DNA at embryonic days (E)14, E17, and E20. Reverse transcriptase/polymerase chain reaction, in situ immunofluorescence, and electron microscopy revealed early lung cell differentiation in both null and wild-type lungs as early as E14. However at E14, myogenin null lungs had decreased 5'-bromo-2-deoxyuridine incorporation compared with that of wild-type littermates, whereas at E17 and E20, increased Bax immunolabeling and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining were detected in the myogenin null mice but not in the wild-type littermates. These observations highlight the importance of skeletal muscle contractile activity in utero for normal lung organogenesis. Null mice lacking the muscle-specific transcription factor myogenin exhibit a secondary effect on lung development such that decreased lung cell proliferation and increased programmed cell death are associated with lung hypoplasia.