Activation of a novel metabolic gene regulatory pathway by chronic
stimulation of skeletal muscle.
Cresci, Sharon, Leon D. Wright, John A. Spratt, F. Norman Briggs, and
Daniel P. Kelly.
Departments of Medicine, and Molecular Biology and Pharmacology,
Washington University School of Medicine, St. Louis, MO 63110; and
Departments of Physiology, and Surgery, Medical College of
Virginia/Virginia Commonwealth University, Richmond, VA 23298
APStracts 2:0405C, 1995.
To determine whether expression of a nuclear gene encoding a
mitochondrial fatty acid oxidation enzyme is regulated in parallel
with skeletal muscle fiber type-specific energy substrate preference,
expression of the gene encoding medium-chain acyl-CoA dehydrogenase
(MCAD) was delineated in canine latissimus dorsi muscle subjected to
chronic motor nerve stimulation. In the predominantly fast-twitch
canine latissimus dorsi muscle, MCAD mRNA levels were regulated by
chronic stimulation in a biphasic pattern. During the first week of
stimulation, steady-state MCAD mRNA levels decreased to 50% of
unstimulated levels. MCAD mRNA levels began to increase during the
third week of stimulation to reach a level 3.0-fold higher than
levels in unstimulated contralateral control muscle by day 70.
Immunodetectable MCAD protein levels paralleled MCAD mRNA levels
throughout the stimulation period. The temporal pattern and magnitude
of MCAD mRNA accumulation in response to muscle stimulation was
distinct from that of mRNAs encoding other enzymes known to be
regulated by this stimulus including glyceraldehyde phosphate
dehydrogenase, citrate synthase, and sarcoplasmic reticulum Ca-ATPase
but paralleled the protein levels of the peroxisome proliferator
activated receptor, an orphan member of the nuclear hormone receptor
superfamily known to regulate genes encoding fatty acid oxidation
enzymes in liver. The skeletal muscle expression pattern of PPAR was
also similar to that of MCAD in unstimulated rat skeletal muscles
with distinct fiber type compositions. These results demonstrate that
a nuclear gene encoding a mitochondrial [beta]-oxidation enzyme is
dynamically regulated in a pattern that parallels skeletal muscle
fiber type-specific energy substrate utilization and implicate an
orphan nuclear receptor transcription factor as a candidate
transducer of this response.
Received 3 April 1995; accepted in final form 6 November 1995.
APS Manuscript Number C183-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 8 December 95