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by MRS non-invasively in the human muscle. It had been long established
by MRS studies that the
31
P spectrum gave very well resolved, strong sig-
nals from ATP and Phosphocreatine in the muscle, as well as from inorganic
phosphate. Guided by the knowledge of the pathway and by the expectation from
MCA that the metabolite concentrations were being regulated during changes
of flux, the
31
P MRS spectrum enabled us to resolve, identify, and quantitate
the glucose-6-phosphate (G-6-P) concentrations under different conditions. The
results basically showed that G-6-P concentrations changed negligibly when the
flux of glycogen synthesis doubled under
in vivo
conditions - a classic case of
Metabolite Control or metabolic Homeostasis (Schafer et al., 2004).
Implications of the methodologies used here for the multilevel concerns of
systemic biology can be derived from experimental results. In general terms
the MRS data showed how the human organism is maintaining constancy of
metabolite concentrations during changes in fluxes. On the physiological level,
the rate of glycogen synthesis serves to maintain constant concentrations of blood
glucose in the face of increased rates of glucose delivery to the blood, generally
by ingestion. (During decreased delivery rates glucose levels are maintained
by hepatic production.) This is an autoregulatory process in which glucose
concentrations drive their uptake and also enhance this flux by stimulating insulin
levels that recruit more transporters. The physiological need for such homeostasis
is known from the pathological consequences of chronic high glucose levels
seen in diabetes.
The biochemical pathway of glycogen synthesis serves this physiological
need by varying its flux in response to the blood glucose levels. Furthermore
biochemical homeostasis, in which pathway intermediates are constant during
changes in flux, is maintained by the complex signaling pathways that regu-
late GSase activity. Therefore, the MRS experiments have explained flux and
metabolic control at both the biochemical level and the higher level of sys-
temic physiology. Most importantly these explanations have been in terms of the
measured,
in vitro
properties of the constituent enzymes, structures, and metabo-
lites - all of which have been thoroughly explored at the molecular level. By the
methodology of
in vivo
MRS coupled with the explanatory concepts of MCA, we
have jumped two levels of explanation, deriving a quantitative understanding of
a major process in systemic physiology from molecular data. The methodology
of these experiments satisfies the criteria established for systemic biology and
has provided prototypical results of the sort expected from this new field.
When one questions the immediate future of these methods it is obvious
that several-fold improvements in the sensitivity and resolution of MRS will
soon be realized, enabling many more pathways to be followed, although there
is no scarcity of possible experiments with present capabilities. Much grander
improvements are being developed in which sensitivity will be increased by
orders of magnitude. These include gains introduced by polarized nuclei or by
