AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling

Abstract

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5' adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors' own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse.

Keywords: AMPK; HDAC4/5; MyHC I(β), motor endplate remodeling; hindlimb suspension; mechanical unloading; p70S6K; soleus muscle.

Figure 1

Key physiological regulators of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity in skeletal muscle and physiologically-relevant AMPK targets. (original scheme)

Figure 2

Hypothetical role of AMPK in the activation of signaling pathways regulating the expression of E3-ubiquitin ligases during gravitational unloading.

Figure 3

The role of AMPK in class IIa histone deacetylases traffic in rat soleus muscle at the initial stages of gravitational unloading (modified from [98]). (A): active muscle; (B): inactive muscle. Time-course studies on the MyHCI (β) expression demonstrate that a reduction in MyHCI (β) mRNA expression begins on the first day of unloading and then steadily decreases during, at least, two weeks of hindlimb unloading [13,14]. As shown in dominant-negative AMPK mutants, AMPK has no effect on the expression of slow MyHC after 14-day unloading [63]. It is clear that an experiment with transgenic animals does not allow for tracing the effect of AMPK on the expression of MyHC at the different time-points of unloading. However, the results of this experiment indicate that the decrease in the expression of slow isoform of MyHC after the completion of the initial stage of hindlimb unloading is determined not by AMPK, but by some other mechanisms, for example, via inhibition of the calcineurin/ Nuclear factor of activated T-cells (NFAT) signaling pathway [14,107].