Kruppel-like factors in muscle health and disease

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Abstract

Kruppel-like factors (KLF) are zinc-finger DNA-binding transcription factors that are critical regulators of tissue homeostasis. Emerging evidence suggests that KLFs are critical regulators of muscle biology in the context of cardiovascular health and disease. The focus of this review is to provide an overview of the current state of knowledge regarding the physiologic and pathologic roles of KLFs in the three lineages of muscle: cardiac, smooth, and skeletal.

Introduction

Cardiovascular disease remains the leading cause of morbidity and mortality in the world [1]. Although recent advances in clinical modalities and pharmacotherapeutics lessen disease burden, a more detailed understanding of molecular mechanisms that drive disease initiation and progression is required for further therapeutic impact. The two predominant cell types in the heart and blood vessels are cardiomyocytes and vascular smooth muscle cells (VSMC), respectively. The primary function of these cell types is contraction, thus enabling sufficient blood flow and oxygenation to peripheral tissues. Dysfunction of muscle leads to a broad spectrum of cardiac and vascular states that can impair their physiologic role. As such, understanding the molecular mechanisms governing cellular function in health and disease is critical for the development of novel therapies.

Section snippets

Kruppel-like factors: General considerations

Kruppel-like factors are members of the zinc-finger class of DNA-binding transcription factors whose name was derived from the German word kruppel (meaning “cripple”) [2]. The original Kruppel gene was identified in Drosophila as a developmental gene critical in early-stage body patterning and segmentation [3]. The first mammalian KLF was identified in 1993, and to date, 18 family members have been identified and numbered chronologically based on their order of discovery [2]. The KLFs share

KLFs and cardiac muscle

Despite the appreciation that transcriptional inputs guide cardiac function in health and disease, the role of KLFs is only beginning to burgeon. This topic was last reviewed seven years ago, and since then, additional evidence has provided mechanistic insights and expanded previously known roles of KLFs in cardiac function while new biologic themes have emerged [4]. As will be discussed below, seminal observations have broadly implicated KLFs as critical mediators of cardiac development,

KLFs and vascular smooth muscle

The principal function of the differentiated vascular smooth muscle cells (VSMC) is contraction to maintain vascular tone for blood flow distribution [50]. This function is coordinated at the molecular level by the expression of multiple contractile proteins, including smooth muscle actin and smooth muscle–myosin heavy chain [50]. However, unlike cardiomyocytes, VSMCs exhibit a high degree of phenotype plasticity, and, in response to acute or chronic injury, are characterized by increased

KLFs and skeletal muscle

Despite the early identification of Kruppel by Ruiz-Gomez et al. [63] nearly two decades ago through myogenic fate mapping studies in gestating flies, the role of KLFs in skeletal muscle has, until recently, been under-developed compared to that of cardiac and smooth muscle. Due to space limitations, we refer the reader to a recent review on the role of KLFs in skeletal muscle biology and will only highlight key insights recently described, as it pertains to myogenesis/muscle fusion and

Concluding remarks

Cardiovascular function is directed by the dynamic interplay between cardiac, smooth, and skeletal muscles. The KLFs have emerged as important regulators of cellular differentiation/proliferation along with various aspects of physiology/pathophysiology in muscle (Fig.). Given that KLFs have been shown to regulate multiple biological processes, it is tempting to speculate that a unifying mechanism that explains diverse cellular effects may be operative. For example, cardiac KLF15 is known to

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