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The MEF2 site is an essential element of muscle enhancers and promoters that is bound by a nuclear activity found, so far, only in muscle and required for tissue-specific transcription. We have cloned a group of transcription factors from human muscle that are responsible for this activity: They are present in muscle-specific DNA-binding complexes, have a target sequence specificity identical to that of the endogenous activity, and are MEF2 site-dependent transcriptional activators. These MEF2 proteins comprise several alternatively spliced isoforms from one gene and a related factor encoded by a second gene. All share a conserved amino-terminal DNA-binding domain that includes the MADS homology. MEF2 transcripts are ubiquitous but accumulate preferentially in skeletal muscle, heart, and brain. Specific alternatively spliced isoforms are restricted to these tissues, correlating exactly with the presence of endogenous MEF2 activity. Furthermore, MEF2 protein is detected only in skeletal and cardiac muscle nuclei and not in myoblast and nonmuscle cells. Thus, post-transcriptional regulation is important in the generation of tissue-specific MEF2 activity. Cardiac and smooth, as well as skeletal, muscles contain functionally saturating levels of MEF2 trans-activating factors that are absent in nonmuscle cells. Moreover, MEF2 is induced in nonmuscle cells by MyoD; however, MEF2 alone is insufficient to produce the full muscle phenotype. Implications for the molecular mechanisms of myogenesis are considered.

Hypertrophy, an increase in cell size without cell division, is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle cells. Cardiac myosins undergo an adult-to-fetal isoform transition in various models of hypertrophy. Using gene-specific cDNA probes, we show here that in the adult myocardium the mRNAs encoding the fetal (skeletal muscle type) isoforms of a-actin and sarcomeric tropomyosin are re-expressed within 2 days in response to pressure overload. In addition, atrial natriuretic factor mRNA, so far believed to be expressed primarily in the atria, was readily detectable in the ventricles of neonates and was induced to markedly high levels in pressure-overloaded adult ventricles. In contrast, cardiac hypertrophy produced by thyroid hormone excess was not associated with induction of the atrial natriuretic factor gene or fetal contractile protein isogenes. Furthermore, the c-fos and c-myc protooncogenes and a major heat shock protein gene (hsp7O) are induced in the ventricular myocardium within 1 hr after imposition of pressure overload. These results suggest that induction of cellular protooncogenes and heat shock (stress) protein genes is an early response to pressure overload, whereas reinduction of the genes normally expressed only in perinatal life, such as fetal isoforms of contractile proteins and atrial natriuretic factor, is a later event. These two types of responses might represent the general pattern of growth induction to work overload by terminally differentiated cells that have lost the ability to undergo DNA replication.The cardiac response to normal growth requirements, as well as to work overload, is dependent on the developmental stage of the organ. During fetal and early postnatal life, the demand for an increased cardiac mass is fulfilled mainly by an increase in the number of preexisting myocytes (hyperplasia), whereas later in life demand for increased mass is fulfilled exclusively by an increase in the size of a fixed number of preexisting myocytes (hypertrophy) (1). Although the most striking feature of the cardiac hypertrophic response is quantitative, resulting in the addition of new sarcomere units within the cell, there are also qualitative changes in the composition of contractile proteins in hypertrophic cells. Myocardial hypertrophy has been shown to be associated with either normal, depressed, or increased contractility, depending on the particular model of hypertrophy studied (2): (i) normal cardiac growth or physiologic hypertrophy from neonatal-to-adult stages, in which the contractility of the myocardium remains normal; (ii) pathologic hypertrophy due to acute pressure overload in which the ventricular weight increases, and the contractility per unit of myocardium is depressed; and (iii) supraphysiologic hypertrophy induced by thyroid hormone excess, in which the increase in myocardial mass is associated with an increase in contractility.It has been previously shown that, in the rat, work overload-induced hypertrophy induces a myosin h...