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LETTER TO THE EDITOR
TO THE EDITOR: Several points need to be made to allow the readers of the Journal of Applied Physiology to put the comments made by Drs. Rennie, Phillips, and Smith (3) into proper context.
1) We will begin by addressing the two specific points raised about methodology. First, the authors of the Letter claim that our original manuscript that introduced the proteolytic methodology did not validate the methodology with measurements that included blood flow and dynamic arteriovenous net balances across the leg. This contention is not correct, as blood flow and net balances were included, and these data and related methods are presented in that manuscript (5). Second, we are acutely aware of the factors that influence the in vivo relative recovery measurement of the compound of interest across the microdialysis membrane (dialysis flow rate, compound size, membrane length, material and pore size, local blood flow, tissue tortuosity, and hydrostatic forces acting on the probe), with compound size being the dominant factor in our use of the methodology. We have confirmed, before completion of our original study, equivalent recovery between labeled histidine and glucose across multiple CMA 60 microdialysis probes placed in human skeletal muscle before and through 24 h after exercise, with periods of varying local muscle blood flow, and under fasting and feeding conditions. Thus it is unlikely our probe recovery estimates influenced the reported results.
2) The statement in the Letter that "leg blood flow... is likely to be depressed" (3) based on the 4-wk unilateral lower limb suspension (ULLS) study by Bleeker et al. (1) is not consistent with the data in the cited study. This paper does not show changes in leg or calf blood flow of the suspended leg compared with control through at least 2 wk of ULLS. In fact, the authors of the paper summarize the influence of unloading on blood flow: "... even in extreme deconditioning due to paralysis after spinal cord injury, with a dramatic decrease in arterial diameter, several studies have reported no differences in resting leg blood flow..." (1). Thus it is unlikely that changes in blood flow influenced our findings.
3) In terms of the percent change calculation and statistical approach, we calculated the change from pre- to post-ULLS for each individual and averaged those numbers to obtain the 44% increase. A standard and accepted t-test was used on the pre- and post-ULLS numbers to obtain the reported statistical difference.
4) We did not intend our statement regarding the use of arteriovenous measurements to suggest these techniques were inappropriate or otherwise should not be used, as we realize the usefulness. However, in relation to our long interest in real and simulated microgravity not all experimental designs allow for the use of these measurements, such as the environment the astronauts are in while on orbit.
5) It should be made clear that the stable isotope methodologies referred to in the Letter measure "mixed muscle" proteolysis, with no discrimination as to which proteins contributed to the measurement. The 3-methylhistidine-based methodology represents the proteolysis of just the two main contractile proteins, myosin and actin. Therefore, it is not surprising that these two different approaches may provide different results as they are not measuring the same thing.
6) Many comments are made in the Letter that are not directly related to the current manuscript (4) and as such are not part of our response. However, it should be clarified that the idea that muscle proteolysis or synthesis is unchanged with aging is not completely consistent with the data in the papers cited in the Letter. One of the papers cited showed a significantly higher mixed muscle proteolysis in the elderly (via arteriovenous balance, one of two techniques used) (6) and a separately cited paper shows a significant depression of muscle synthesis with aging (2).
Additional comments. We would like to highlight that we have completed a comprehensive analysis of molecular factors that regulate muscle protein breakdown and synthesis from biopsy samples taken before and after the 3-day ULLS period from the same subjects reported in the manuscript under discussion. These data provide strong support to the microdialysis findings and the general idea presented in the current manuscript that proteolysis of skeletal muscle is increased during the early phase of unloading (Gustafsson T, Osterlund T, von Walden F, Trappe TA, Linnehan RM, Tesch PA, unpublished observations/data).
We appreciate the opportunity to provide a more complete record of the methodology and our findings, and a more balanced and factual presentation of the cited literature. This exchange highlights the importance of continued investigation into human skeletal muscle proteolysis, including the development of new and innovative methods.
FOOTNOTES
Address for reprint requests and other correspondence: P. A. Tesch, Dept. of Health Science, Mid Sweden Univ., SE-83125 Östersund, Sweden (e-mail: Per.Tesch{at}miun.se)
REFERENCES
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