Haplodeficiency of Hexim1 Enhances Skeletal Muscle Regeneration by Promoting Satellite Cell Post-Injury Expansion

Abstract

Skeletal muscle constitutes the most abundant tissue of the human body and possesses remarkable regeneration capacity for the repair of muscle damage in injury or muscular disorders. However, the regeneration capacity of skeletal muscle varies depending on a number of factors, including age, anatomic location and the local tissue environment. Loss of muscle regeneration capacity, such as that seen in dystrophic muscle diseases characterized by progressive muscle degeneration and weakness, leads to reduced mobility and pre-mature death.

Hexamethylene bis-acetamide inducible 1 (HEXIM1, aka cardiac lineage protein 1, CLP-1) is a well-established inhibitory component of the positive transcription elongation factor (P-TEFb) complex. Our lab has previously reported that down-regulation of HEXIM1 in mouse myoblast cell line C2C12 inhibits myogenic differentiation. Since myogenic differentiation of muscle progenitor cells is a critical event of skeletal muscle regeneration, I hypothesize that HEXIM1 can regulate the myogenic differentiation of muscle progenitor cells, the satellite cells, via the P-TEFb-dependent transcription elongation process and thus influence the regeneration of skeletal muscle.

By application of an established skeletal muscle acute injury and regeneration model, I observed enhanced regeneration of muscle fibers and improved recovery of muscle contractile function following acute injury in Hexim1 haplodeficient mice in comparison with wild type controls. Immunofluorescence-based cell counting and flow cytometry analysis both showed that Hexim1 haplodeficient muscles harbored more satellite cells than wild type controls during regeneration. Hexim1 haplodeficient satellite cells proliferate faster than wild type satellite cells in vitro and are resistant to low-serum induced myogenic differentiation. Transplantation of Hexim1 haplodeficient satellite cells into injured wild type muscles improved regeneration more effectively than transplantation of wild type satellite cells. Conversely, HMBA induced HEXIM1 overexpression repressed satellite cell proliferation, induced myogenic differentiation and restrained muscle regeneration. This study would establish HEXIM1/P-TEFb pathway as a regulator of skeletal muscle regeneration and satellite cell maintenance, and may offer a valuable approach of modulating HEXIM1 to enhance cell-based therapies for muscular disorders.