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PERSPECTIVES |
1 Department of Kinesiology and Program in Neuroscience, The College of William & Mary, Williamsburg, VA 23187-8795, USA E-mail:mrdesc{at}wm.edu
The loss of skeletal muscle mass has been shown to have serious health implications. For example, decreased muscle size – atrophy – has been linked with osteoporosis, type II diabetes, cachexia, and among the aged a greater incidence of falls (see Janssen & Ross, 2005). As a result, gaining a clear understanding of the molecular and cellular mechanisms that trigger muscle atrophy has become a vital health initiative. Although a recent report (Edstrom et al. 2006) suggests that a different mechanism is responsible for sarcopaenia, or age-related loss of muscle size, a convincing body of evidence has identified the ubiquitin proteosome pathway as a major regulator of the sequence of events leading to the degradation of contractile proteins in adult muscle. Crucial constituents of this pathway are ligases that tag specific proteins for degradation and insert those tagged proteins into the proteosome complex, as well as peptides that comprise the body of the proteosome, where the actual degradation occurs.
Seminal work by Bodine et al. (2001) demonstrated that among rats experiencing muscle atrophy as a result of a number of different disuse models including denervation, limb immobilization, and muscle unloading, the genetic expression of several important components of the ubiquitin pathway was up-regulated. Subsequent research by Lecker et al. (2004) amplified those findings by determining that atrophic muscles in rats afflicted with cancer, diabetes, or renal failure also exhibited an increased expression of genes of the ubiquitin pathway. Combined, these data suggest that in non-sarcopaenic, skeletal muscle tissue of animals, atrophy shares a common regulatory pathway triggering protein degradation regardless of the stimulus inducing that condition.
As convincing as this evidence is, very little of it has been generated by examining atrophying human skeletal muscle, nor is there much evidence regarding changes in expression of the ubiquitin pathway at the protein level. In the current issue of The Journal of Physiology, Urso et al. (2007) provide compelling evidence that not only does the ubiquitin proteolytic pathway function as a vital regulatory mechanism during the early stages of muscle atrophy among humans, but also that the location of these newly synthesized protein products indicates that muscle degradation in those early stages of atrophy occurs mainly at the cell's sarcolemma and extracellular matrix. Gaining access to rare muscle samples obtained from patients 2 and 5 days following spinal cord injury, these investigators have expanded our understanding by examining not only alterations in genetic expression, but also protein content and location by using a combination of analytical techniques including microarray analysis, quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Using this methodology, the research team found an increase in gene expression for components of the ubiquitin pathway. Western blots, however, were unable to detect a significant increase in ubiquitin protein content in tissue homogenates of muscle samples collected at 2 and 5 days post-injury. It was using immunohistochemistry that the authors arrived at their most novel and insightful results. Due to the in situ nature of immunohistochemical procedures, it was revealed that at 5 days, but not 2 days, following injury, there was a greater expression of ubiquitin pathway proteins. Importantly, these newly synthesized products were concentrated at the periphery of the muscle cell. This suggests that at least the earliest events of protein degradation during muscle atrophy take place in the region of the cell's sarcolemma.
Important features distinguish the article published in this issue of The Journal of Physiology (Urso et al. 2007) from others published on the same topic. The first is that it examines human muscle tissue in the earliest stages of atrophy following spinal cord injury, a traumatic and acute denervating event (as opposed to the gradual onset of denervation resulting from neurodegenerative diseases) leading to muscle disuse. Another is the use of several analytical methods enabling an assessment of early atrophic responses and their regulatory mechanisms at the levels of genetic expression, protein content and intracellular location of newly synthesized proteins. Owing to these distinguishing features, significant advances in our understanding of muscle atrophy have been made by the authors. We have learned that (1) following a severe atrophic stimulus of sudden onset such as spinal cord injury, the ubiquitin proteosome pathway in human muscle is rapidly activated (i.e. within 5 days) showing increases in mRNA and protein expression; (2) different analytical techniques may yield different results (i.e. Western blots versus immunohistochemistry) when examining the same variable of interest – this should give pause to scientists making broad, definitive conclusions about complex biological phenomena based upon the results of a single analytical technique; and (3) the site of protein degradation during early stages of muscle atrophy is the cell's sarcolemma and its extracellular matrix. Moreover, a broader lesson concerning scientific investigation may be learned, as well, that perhaps it is the location, or translocation, of proteins within the cell that has a greater biological impact than changes in the gross, total content of that protein within the cell.
The findings of Urso et al. (2007) that are reported here principally contribute to our understanding of the basic mechanisms involved in regulating muscle atrophy. It is reasonable, however, to predict that this knowledge will some day be valuable to health care professionals attempting to mitigate, or even prevent, the loss of muscle mass that accompanies various forms of disuse and leads to serious morbidities.
References
Edstrom E, Altun M, Hagglund M & Ulfhake B (2006). J Gerontol Biol Sci Med Sci 61, 663–674.
Janssen I & Ross R (2005). J Nutr Health Aging 9, 408–419.[Medline]
Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE & Goldberg AL (2004). FASEB J 18, 39–51.
Urso ML, Chen YW, Scrimgeour AG, Lee PC, Lee KF & Clarkson PM (2007). J Physiol 579, 877–892.
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