The myonuclear domain is not maintained in skeletal muscle during either atrophy or programmed cell death

Abstract

Skeletal muscle mass can increase during hypertrophy or decline dramatically in response to normal or pathological signals that trigger atrophy. Many reports have documented that the number of nuclei within these cells is also plastic. It has been proposed that a yet-to-be-defined regulatory mechanism functions to maintain a relatively stable relationship between the cytoplasmic volume and nuclear number within the cell, a phenomenon known as the "myonuclear domain" hypothesis. While it is accepted that hypertrophy is typically associated with the addition of new nuclei to the muscle fiber from stem cells such as satellite cells, the loss of myonuclei during atrophy has been controversial. The intersegmental muscles from the tobacco hawkmoth Manduca sexta are composed of giant syncytial cells that undergo sequential developmental programs of atrophy and programmed cell death at the end of metamorphosis. Since the intersegmental muscles lack satellite cells or regenerative capacity, the tissue is not "contaminated" by these nonmuscle nuclei. Consequently, we monitored muscle mass, cross-sectional area, nuclear number, and cellular DNA content during atrophy and the early phases of cell death. Despite a ∼75-80% decline in muscle mass and cross-sectional area during the period under investigation, there were no reductions in nuclear number or DNA content, and the myonuclear domain was reduced by ∼85%. These data suggest that the myonuclear domain is not an intrinsic property of skeletal muscle and that nuclei persist through atrophy and programmed cell death.

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

“…However, linkage of myonuclei number and muscle fiber size is the basis of the “myonuclear domain” hypothesis which asserts that a single myonucleus controls the translational and transcriptional regulation of protein synthesis for a limited cell volume known as the myonuclear domain. Although more recent studies indicate that age‐related myofiber atrophy results primarily from reductions in myonuclear domain size instead of the loss of myonuclei numbers (Karlsen et al, 2015; Schwartz, Brown, McLaughlin, Smith, & Bigelow, 2016), other findings show that increased myonuclear fusion facilitates muscle hypertrophy, especially when the myonuclear domain size exceeds a certain threshold (Jo et al, 2012; Petrella, Kim, Cross, Kosek, & Bamman, 2006). The findings in the current study support the possibility that the ablation of TNF‐α contributes to increased myofiber size in aging muscle by increasing the frequency of muscle cell fusion with aging muscle fibers.…”

Skeletal Muscles Do not Undergo Apoptosis During Either Atrophy or Programmed Cell Death

“…The plastic nature of muscle, and its syncytial status, has given rise to a controversy in the field that only recently appears to have been resolved-the "myonuclear domain hypothesis" [7][8][9]. This theory has its origins in the concept of "Wirkungssphäre, " or "sphere of influence," proposed by Strassburger in 1893 [10], in which he argued that a nucleus can only support a descrete volume of cytoplasm, which in turn defines the upper limits to cell size.…”

“…We used two independent methods to monitor nuclear fate during both atrophy and death in this model [7]. The first was a standard anatomical approach.…”

“…When the ISMs undergo atrophy and death, there are dramatic reductions in both the volume and crosssectional area of the fibers, but grossly, the number of nuclei was unchanged (Figures 3 and 4). Using sectioned tissues for quantitative studies, we found that there was a ~49% reduction in fiber crosssectional area during atrophy and a further 30% decline during the early stages of death ( [7]; Figure 4). However, the number of nuclei did not change during this same period meaning that there was functionally an 84% reduction in the myonuclear domain.…”

“…The second method we employed to monitor the fate of the nuclei within the ISMs was to measure the DNA content of individual muscle fibers from animals on day 13, when the muscles are homeostatic until 18 h after adult eclosion, when the muscles were highly degenerate [7]. We quantified the DNA content of 420 individual cells and found that there was no significant loss during development.…”