# SKELETAL MUSCLE ENERGY METABOLISM

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 1992 · $244,746

## Abstract

The cellular bioenergetic status, often compromised in a wide range of
disease states, may play a more active role in the regulation of cellular
processes than previously thought.  The state of muscle energetics, which
can be defined by the chemical potential of ATP (muATP), is viewed as the
medium through which two important cell functions are regulated:
mitochondrial respiration and muscle phenotypic expression.  Contractile
activity induces changes in muATP and thus the position of equilibrium of
the creatine kinase (CK) reaction.  Cytoplasmic signals, regulating the
mitochondria in the steady state, match the rate of oxygen consumption to
the rate of ATP utilization.  The signal was thought to be the
concentration of ADP in a negative feedback manner, but recent data
indicate the regulation of oxidative phosphorylation in skeletal muscle and
other cells is more involved both in detail and concept.  Our recent
results indicate that altered bioenergetic states induced by competitively
inhibiting CK activity in vivo also alter skeletal muscle phenotype.  The
new concept imagined is that muATP remains high when contractile activity
is low, and this physiological state requires only a simple feedback
regulation of respiration and leads to a fast muscle phenotype.  In
contrast, high contractile activity increases the ATPase drain on muATP and
influences an additional feedforward respiratory control mechanism; this
physiological state leads to a slow muscle phenotype.  This view leads to
several new hypotheses and will require a more rigorous test of CK
function.  It offers the possibility of a synthesis of cellular
bioenergetics in that the cytoplasmic content of "high energy phosphates"
of a skeletal muscle cell may regulate cellular respiration and also play
an important role in longer term adaptations.  We set our specific aims as
three hypotheses that define and test these concepts:  1.  We propose to
test the hypothesis that the kinetics under homogenous in vitro conditions
are different from those in isolated mouse extensor digitorum longus (EDL)
and soleus (SOL) muscles by measuring the forward and reverse fluxes
between PCr and gammaATP catalyzed by CK in homogeneous solutions of
reactants and enzyme designed to mimic the cytoplasmic milieu.  2.  We
propose to test that the negative feedback by ADP on mitochondria predicts
the kinetics of recovery metabolism (31P NMR for high-energy phosphates and
polarography for O2 consumption) in fast-twitch skeletal muscle, but that
additional mechanisms are involved in slow-twitch muscle.  Secondly, we
will test the hypothesis that these kinetics are influenced by the type of
metabolic substrate such that ADP acts as a fine control (which may be
sufficient for certain cell types or physiological situations) with an
additional feedforward control in certain cells.  Thus these experiments
introduce the concept of feedforward regulation of oxidative
phosphorylation in addition to the classical feedback re...

## Key facts

- **NIH application ID:** 3157527
- **Project number:** 5R01AR036281-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **SAM.gov UEI:** HD1WMN6945W6
- **Principal Investigator:** Martin J Kushmerick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $244,746
- **Award type:** 5
- **Project period:** 1988-10-01 → 1996-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3157527

## Citation

> US National Institutes of Health, RePORTER application 3157527, SKELETAL MUSCLE ENERGY METABOLISM (5R01AR036281-08). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3157527. Licensed CC0.

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