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Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs
Gluconeogenesis and Endurance Exercise Capacity in Mice.
Authors Martino MR, Habibi M, Ferguson D, Brookheart RT, Thyfault JP, Meyer GA, Lantier
L, Hughey CC, Finck BN
Submitted By Submitted Externally on 3/15/2024
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2024
Date Published 2/1/2024
Volume : Pages Not Specified : Not Specified
PubMed Reference 38353639
Abstract Exercise robustly increases the glucose demands of skeletal muscle. This demand
is met not only by muscle glycogenolysis, but also by accelerated liver glucose
production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical
work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during
exercise is dependent on highly coordinated responses within and between muscle
and liver. Specifically, exercise increases the rate at which gluconeogenic
precursors such as pyruvate/lactate or amino acids are delivered from muscle to
the liver, extracted by the liver, and channeled into glucose. Herein, we
examined the effects of interrupting gluconeogenic efficiency and capacity on
exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2)
and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or
ALT2 alone did not significantly affect time to exhaustion or post-exercise
glucose concentrations in treadmill exercise tests, but mice lacking both MPC2
and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower
circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux
analyses demonstrated that DKO mice exhibited lower endogenous glucose
production owing to decreased glycogenolysis and gluconeogenesis at rest and
during exercise. The decreased gluconeogenesis was accompanied by lower
anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings
demonstrate that the transition of the liver to the gluconeogenic mode is
critical for preventing hypoglycemia and sustaining performance during exercise.
The results also illustrate the need for interorgan crosstalk during exercise as
described by the Cahill and Cori cycles.


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