Evidence that satellite cell decrement contributes to preferential decline in nuclear number from large fibres during murine age-related muscle atrophy

Abstract

Skeletal muscle fibres are multinucleate syncitial cells that change size during adult life depending on functional demand. The relative contribution of change in nuclear number and/or cell growth to fibre size change is unclear. We report that nuclei/unit length decreases in larger fibres during skeletal muscle ageing. This leads to an increased size of nuclear domain (quantity of cytoplasm/number of nuclei within that cytoplasm). Initially, larger fibres have more satellite cells than small fibres, but this advantage is lost as satellite cells decline with age. These changes are accompanied by an overall decline in fibre size, returning domain size to the normal range. Exacerbated loss of fibre nuclei per unit length during ageing of myoD-null mice provides the first experimental support for the hypothesis that a satellite cell defect causes inadequate nuclear replacement. We propose a model in which a decline in satellite cell function and/or number during ageing leads to a loss of nuclei from large fibres and an associated domain size increase that triggers cytoplasmic atrophy through the normal cell-size-regulating machinery.

Myeloid cell‐derived tumor necrosis factor‐alpha promotes sarcopenia and regulates muscle cell fusion with aging muscle fibers

“…Although the age‐related decline in satellite cell number contributes to the reduced regenerative capacity of injured, aging muscle (Brack, Bildsoe, & Hughes, 2005; Fry et al, 2015), whether satellite cell loss is sufficient to cause reduction in muscle mass in uninjured, aging muscle is controversial. Targeted ablation of Pax7+ satellite cells that produced a lifelong reduction in satellite cell numbers by approximately 70%–90% did not increase sarcopenia in sedentary mice (Fry et al, 2015) and findings in the current study show that satellite cell numbers can be reduced by about 45% in aging muscle, which leads to a reduction in sarcopenia.…”

When stem cells grow old: phenotypes and mechanisms of stem cell aging

“…Unlike HSCs and ISCs, the frequency of satellite cells decreases with age (Brack et al, 2005;Collins et al, 2007;Gibson and Schultz, 1983). The in vitro proliferation rate and the in vivo engraftment and regeneration potential of satellite cells upon transplantation also decline with age (Bernet et al, 2014;Bortoli et al, 2003;Collins et al, 2007;Cosgrove et al, 2014;Sousa-Victor et al, 2014).…”

Molecules in motion: influences of diffusion on metabolic structure and function in skeletal muscle

“…The myonuclear domain has often been considered to be conserved in skeletal muscle, including during increases or decreases in fiber size (e.g. Allen et al, 1995;Roy et al, 1999;Bruusgaard et al, 2003;Bruusgaard et al, 2006;Brack et al, 2005), although this notion does not seem to be generally applicable and remains the source of debate (reviewed in Gundersen and Bruusgaard, 2008). Nevertheless, the size of the myonuclear domain presumably is regulated to ensure sufficient transcriptional capacity as well as limited distances over which nuclear substrates and products must travel to reach sites of action.…”