HDACs in Fiber Type Specification

Inactivation of HDAC genes in mouse models have been performed for all class I and class IIa HDACs. HDAC4-null mice die shortly after birth with labored breathing due to abnormal ossification of the rib cage (Vega et al. 2004), whereas HDAC5- and HDAC9-null mice are viable, but develop cardiac hypertrophy due to increased responsiveness to calcineurin-mediated MEF2 transcriptional activation (Zhang et al. 2002b; Chang et al. 2004). In HDAC4, HDAC5, and HDAC9-null mouse models, there was no report of any grossly abnormal skeletal muscle phenotype (Potthoff et al. 2007a). However, analysis of class IIa HDAC mutant mice revealed that a combined inactivation of any two class IIa HDACs (HDAC4, -5, or -9) lead to an increase in type I slow-oxidative muscle fiber composition while skeletal muscle development proceeds normally (Potthoff et al. 2007a). These findings reveal that class IIa HDACs play an instructive but redundant role in muscle fiber type specification. The aberrant induction of type I fibers in class IIa HDAC mutant skeletal muscle could explain the observation that MEF2 is more active in slow-oxidative fibers than fast-glycolytic fibers. Potthoff et al. further reported that class IIa HDACs are selectively targeted for degradation in slow-oxidative fibers, resulting in greater MEF2 activity (Potthoff et al. 2007a). However, in a report by Cohen et al., no apparent difference in HDAC4 levels was observed in soleus (oxidative) vs. tibialis anterior (TA) (glycolytic) muscle.

Interestingly, the apparent mobility of HDAC4 is slower in oxidative fibers than in glycolytic fibers, suggesting a differential modification (Cohen et al. 2007). This mobility shift of HDAC4 is associated with hyperphosphorylation on serine 467, a major target of CaMKII (Backs et al. 2006). The latter result indicates that HDAC4 is differentially phosphorylated, possibly by CaMKII, in myofibers of different contractility and metabolic properties. Indeed, in cultured skeletal muscle fibers, repetitive slow fiber-type electrical stimulation, but not fast fiber type stimulation, induced HDAC4 phosphorylation and translocation from the nucleus to the cytoplasm in a CaMK-dependent manner (Liu et al. 2005). Similarly, the exercise-induced myofiber transition from type IIb to type IIa involves a concurrent activation of MEF2-dependent transcription and nuclear export of HDAC4 and HDAC5, a process that could involve both AMPK and CaMKII (McGee et al. 2009). Supporting this conclusion, when a HDAC5 mutant resistant to phosphory-lation is expressed in skeletal muscle, exercise-induced fiber-type switching from fast-glycolytic to slow-oxidative fibers is suppressed. Thus, activity-dependent phosphorylation, subcellular localization and/or degradation of class IIa HDAC members could all contribute to myofiber specification and remodeling.

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