Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle

Abstract

Disruptions in the use of skeletal muscle lead to muscle atrophy. After short periods of disuse, muscle atrophy is reversible, and even after prolonged periods of inactivity, myofiber degeneration is uncommon. The pathways that regulate atrophy, initiated either by peripheral nerve damage, immobilization, aging, catabolic steroids, or cancer cachexia, however, are poorly understood. Previously, we found that Runx1 (AML1), a DNA-binding protein that is homologous to Drosophila Runt and has critical roles in hematopoiesis and leukemogenesis, is poorly expressed in innervated muscle, but strongly induced in muscle shortly after denervation. To determine the function of Runx1 in skeletal muscle, we generated mice in which Runx1 was selectively inactivated in muscle. Here, we show that Runx1 is required to sustain muscle by preventing denervated myofibers from undergoing myofibrillar disorganization and autophagy, structural defects found in a variety of congenital myopathies. We find that only 29 genes, encoding ion channels, signaling molecules, and muscle structural proteins, depend upon Runx1 expression, suggesting that their misregulation causes the dramatic muscle wasting. These findings demonstrate an unexpected role for electrical activity in regulating muscle wasting, and indicate that muscle disuse induces compensatory mechanisms that limit myofiber atrophy. Moreover, these results suggest that reduced muscle activity could cause or contribute to congenital myopathies if Runx1 or its target genes were compromised.

Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model

“…More than 20 transcriptional and growth factors were significantly upregulated in the masseter in response to the ICU intervention. The 12-fold upregulation of RUNX1, essential in preventing myofibrillar disorganization and severe muscle wasting, supports the activation of specific pathways compensating for the negative effects of the ICU intervention in masticatory muscles and preventing or reducing myofibrillar disorganization and muscle atrophy (68). In different denervation models, HDAC4 has been shown to be a critical negative regulator of MEF2, leading to muscle dysfunction (14).…”

Different autonomous myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse embryogenesis

“…To investigate whether all muscle cells were derived from Myf5-expressing cells (referred to as Myf5-derived cells in this paper) or whether the Myf5 lineage contributes to the cellular heterogenity of muscular cells, as suggested by previous experiments using ES-cell derived skeletal myocytes (Braun and Arnold, 1996), we crossed Myf5-Cre mice, which carry a Crerecombinase inserted into the Myf5 locus (Tallquist et al, 2000), with a Rosa26lacZ Cre-reporter strain (Soriano, 1999). The same Myf5-Cre strain has been employed in a number of studies to trace Myf5-expressing cells in satellite cells of adult mice (Kuang et al, 2007) or to delete genes in skeletal muscle (Wang et al, 2005). A strong expression of the lacZ reporter gene was observed at E10.5 ( Fig.…”

Runx1 modulates developmental, but not injury-driven, hair follicle stem cell activation

“…Runx1 is mutated in 20-30% of individuals with acute myeloid leukemia and myelodysplastic syndrome (Coffman, 2003;Wang et al, 2006), and affects cell survival, proliferation and differentiation (Blyth et al, 2005;Mikhail et al, 2006). Runx1 also plays roles in muscle (Wang et al, 2005), nervous system (Theriault et al, 2005;Chen et al, 2006) and skin, where it affects hair follicle (HF) shaft structure (Raveh et al, 2006). The role of Runx1 in HFSCs is unknown.…”