Am J Physiol Cell Physiol AJP: Heart and Circulatory Physiology
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Am J Physiol Cell Physiol 296: C1040-C1048, 2009. First published March 18, 2009; doi:10.1152/ajpcell.00475.2008
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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Mitogen-activated protein kinase signaling is necessary for the maintenance of skeletal muscle mass

Hao Shi,1 Jason M. Scheffler,1 Caiyun Zeng,1 Jonathan M. Pleitner,1 Kevin M. Hannon,2 Alan L. Grant,1 and David E. Gerrard1

Departments of 1Animal Sciences and 2Basic Medical Sciences, Purdue University, West Lafayette, Indiana

Submitted 17 September 2008 ; accepted in final form 6 March 2009

The signal transduction cascades that maintain muscle mass remain to be fully defined. Herein, we report that inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in vitro decreases myotube size and protein content after 3-day treatment with a MEK inhibitor. Neither p38 nor JNK inhibitors had any effect on myotube size or morphology. ERK1/2 inhibition also upregulated gene transcription of atrogin-1 and muscle-specific RING finger protein 1 and downregulated the phosphorylation of Akt and its downstream kinases. Forced expression of enhanced green fluorescent protein-tagged MAPK phosphatase 1 (MKP-1) in soleus and gastrocnemius muscles decreased both fiber size and reporter activity. This atrophic effect of MKP-1 was time dependent. Analysis of the reporter activity in vivo revealed that the activities of nuclear factor-{kappa}B and 26S proteasome were differentially activated in slow and fast muscles, suggesting muscle type-specific mechanisms may be utilized. Together, these findings suggest that MAPK signaling is necessary for the maintenance of skeletal muscle mass because inhibition of these signaling cascades elicits muscle atrophy in vitro and in vivo.

myocyte; signal transduction; muscle atrophy


Address for reprint requests and other correspondence: D. E. Gerrard, Dept. of Animal Sciences, Purdue Univ., 915 W. State St., West Lafayette, IN 47907 (e-mail: dgerrard{at}purdue.edu)






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