PGC-1α4 gene expression is suppressed by the IL-6-MEK-ERK 1/2 MAPK signalling axis and altered by resistance exercise, obesity and muscle injury.
PGC-1α4 is a novel regulator of muscle hypertrophy; however, there is limited understanding of the regulation of its expression and role in many (patho)physiological conditions. Therefore, our purpose was to elicit signalling mechanisms regulating gene expression of Pgc1α4 and examine its response to (patho)physiological stimuli associated with altered muscle mass.



IL-6 knockout mice and pharmacological experiments in C2C12 myocytes were used to identify regulation of Pgc1α4 transcription. To examine Pgc1α4 gene expression in (patho)physiological conditions, obese and lean Zucker rats with/without resistance exercise (RE), ageing mice and muscle regeneration from injury were examined.



In IL-6 knockout mice, Pgc1α4mRNA was ~sevenfold greater than wild type. In C2C12 cells, Pgc1α4mRNA was suppressed ~70% by IL-6. Suppression of Pgc1α4 by IL-6 was prevented by MEK-ERK-MAPK inhibition. RE led to ~260% greater Pgc1α4mRNA content in lean rats. However, obese Zucker rats exhibited ~270% greater Pgc1α4mRNA than lean, sedentary with no further augmentation by RE. No difference was seen in IL-6mRNA or ERK-MAPK phosphorylation in Zucker rats. Aged mice demonstrated ~50% lower Pgc1α4mRNA and ~fivefold greater ERK-MAPK phosphorylation than young despite unchanged Il-6mRNA. During muscle regeneration, Pgc1α4 content is ~30% and IL-6mRNA >threefold of uninjured controls 3 days following injury; at 5 days, Pgc1α4 was >twofold greater in injured mice with no difference in IL-6mRNA.



Our findings reveal a novel mechanism suppressing Pgc1α4 gene expression via IL-6-ERK-MAPK and suggest this signalling axis may inhibit Pgc1α4 in some, but not all, (patho)physiological conditions.
Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
J L
JL
Brown
Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
M E
ME
Rosa-Caldwell
Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
D E
DE
Lee
Exercise Muscle Biology Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
L A
LA
Brown
Exercise Muscle Biology Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
R A
RA
Perry
Muscle Biology Laboratory, Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA.
K L
KL
Shimkus
Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
T A
TA
Blackwell
Muscle Biology Laboratory, Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA.
J D
JD
Fluckey
Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, SC, USA.
J A
JA
Carson
Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, USA.
S
S
Dridi
Exercise Muscle Biology Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
T A
TA
Washington
Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
N P
NP
Greene
D000375:Aging / Q000502:physiology; D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000293:injuries / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000096:biosynthesis*; D010805:Physical Conditioning, Animal / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology*
C508600:IL6 protein, human; D015850:Interleukin-6; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat

JNK
; 
MEK
; C2C12; PGC-1α; p38; skeletal muscle