TY - JOUR

T1 - SIRT1 regulates nuclear number and domain size in skeletal muscle fibers

AU - Ross, Jacob A

AU - Levy, Yotam

AU - Svensson, Kristoffer

AU - Philp, Andrew

AU - Schenk, Simon

AU - Ochala, Julien

N1 - © 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

PY - 2018/9

Y1 - 2018/9

N2 - Skeletal muscle fibers are giant multinucleated cells wherein individual nuclei govern the protein synthesis in a finite volume of cytoplasm; this is termed the myonuclear domain (MND). The factors that control MND size remain to be defined. In the present study, we studied the contribution of the NAD+ -dependent deacetylase, sirtuin 1 (SIRT1), to the regulation of nuclear number and MND size. For this, we isolated myofibers from mice with tissue-specific inactivation (mKO) or inducible overexpression (imOX) of SIRT1 and analyzed the 3D organisation of myonuclei. In imOX mice, the number of nuclei was increased whilst the average MND size was decreased as compared to littermate controls. Our findings were the opposite in mKO mice. Muscle stem cell (satellite cell) numbers were reduced in mKO muscles, a possible explanation for the lower density of myonuclei in these mice; however, no change was observed in imOX mice, suggesting that other factors might also be involved, such as the functional regulation of stem cells/muscle precursors. Interestingly, however, the changes in the MND volume did not impact the force-generating capacity of muscle fibers. Taken together, our results demonstrate that SIRT1 is a key regulator of MND sizes, although the underlying molecular mechanisms and the cause-effect relationship between MND and muscle function remain to be fully defined.

AB - Skeletal muscle fibers are giant multinucleated cells wherein individual nuclei govern the protein synthesis in a finite volume of cytoplasm; this is termed the myonuclear domain (MND). The factors that control MND size remain to be defined. In the present study, we studied the contribution of the NAD+ -dependent deacetylase, sirtuin 1 (SIRT1), to the regulation of nuclear number and MND size. For this, we isolated myofibers from mice with tissue-specific inactivation (mKO) or inducible overexpression (imOX) of SIRT1 and analyzed the 3D organisation of myonuclei. In imOX mice, the number of nuclei was increased whilst the average MND size was decreased as compared to littermate controls. Our findings were the opposite in mKO mice. Muscle stem cell (satellite cell) numbers were reduced in mKO muscles, a possible explanation for the lower density of myonuclei in these mice; however, no change was observed in imOX mice, suggesting that other factors might also be involved, such as the functional regulation of stem cells/muscle precursors. Interestingly, however, the changes in the MND volume did not impact the force-generating capacity of muscle fibers. Taken together, our results demonstrate that SIRT1 is a key regulator of MND sizes, although the underlying molecular mechanisms and the cause-effect relationship between MND and muscle function remain to be fully defined.

KW - Animals

KW - Cell Count

KW - Cell Nucleus/metabolism

KW - Cell Nucleus Size

KW - Mice, Knockout

KW - Muscle Fibers, Skeletal/metabolism

KW - Satellite Cells, Skeletal Muscle/pathology

KW - Sirtuin 1/metabolism

U2 - 10.1002/jcp.26542

DO - 10.1002/jcp.26542

M3 - Journal article

C2 - 29574748

VL - 233

SP - 7157

EP - 7163

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 9

ER -