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Review
. 2023 Dec 10;12(24):2811.
doi: 10.3390/cells12242811.

The Structural Adaptations That Mediate Disuse-Induced Atrophy of Skeletal Muscle

Ramy K A Sayed  1   2   3 , Jamie E Hibbert  1   2 , Kent W Jorgenson  1   2 , Troy A Hornberger  1   2
Affiliations
Review

The Structural Adaptations That Mediate Disuse-Induced Atrophy of Skeletal Muscle

Ramy K A Sayed et al. Cells. .

Abstract

The maintenance of skeletal muscle mass plays a fundamental role in health and issues associated with quality of life. Mechanical signals are one of the most potent regulators of muscle mass, with a decrease in mechanical loading leading to a decrease in muscle mass. This concept has been supported by a plethora of human- and animal-based studies over the past 100 years and has resulted in the commonly used term of 'disuse atrophy'. These same studies have also provided a great deal of insight into the structural adaptations that mediate disuse-induced atrophy. For instance, disuse results in radial atrophy of fascicles, and this is driven, at least in part, by radial atrophy of the muscle fibers. However, the ultrastructural adaptations that mediate these changes remain far from defined. Indeed, even the most basic questions, such as whether the radial atrophy of muscle fibers is driven by the radial atrophy of myofibrils and/or myofibril hypoplasia, have yet to be answered. In this review, we thoroughly summarize what is known about the macroscopic, microscopic, and ultrastructural adaptations that mediated disuse-induced atrophy and highlight some of the major gaps in knowledge that need to be filled.

Keywords: disuse; fascicle; hypoplasia; longitudinal atrophy; muscle fibers; myofibril; myofilaments; radial atrophy; sarcomere.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of skeletal muscle structure. (A) Illustration of major structural components of skeletal muscle. (B) Immunohistochemical staining (IHC) of a mouse plantaris muscle cross-section for laminin (white) as well as Type IIA (cyan) and Type IIB muscle fibers (magenta) were used to highlight the endomysium that surrounds individual muscle fibers. (C) IHC of a tibialis anterior muscle cross-section was used to identify a major component of the endomysium (laminin, white), a marker of satellite cells (Pax7, red), and nuclei (green). (D,E) Electron microscopy of mouse plantaris muscle cross-section was used to highlight the sarcoplasmic reticulum (SR) and mitochondria (mito) that surround individual myofibrils. (E) Higher magnification of the boxed region in (D) reveals the presence of the myosin (thick) and actin (thin) myofilaments. The figure is adapted from Jorgenson et al., 2020 [32].
Figure 2
Figure 2
Illustration of how longitudinal and radial atrophy of fascicles could influence the structural adaptations observed at the whole muscle level. (A) Description of a hypothetical muscle and its basic architectural properties. The geometric model of Maxwell et al. (1974) [108] was used to predict how only a 25% decrease in fascicle diameter (B), or only a 25% decrease in fascicle length (C), would impact measurements of whole muscle length and whole muscle diameter. (D) Prediction of how a 25% decrease in fascicle length plus a 14% decrease in whole muscle length would impact the whole muscle diameter and pennation angle of the fascicles. (E) Prediction of how a 25% decrease in fascicle diameter would impact the whole muscle diameter and pennation angle of the fascicles when whole muscle length is fixed.
Figure 3
Figure 3
Illustration of the mechanisms that could lead to radial atrophy of fascicles. (A) Radial atrophy of muscle fibers, (B) muscle fiber hypoplasia, and (C) longitudinal atrophy of muscle fibers that exhibit intrafascicular terminations such as those found in the sartorius and gracilis muscles of humans [120,124]. The figure is adapted from Jorgenson et al., 2020 [32].
Figure 4
Figure 4
Illustration of how changes in fiber length and fiber CSA can alter the number of muscle fibers that appear in a mid-belly cross-section. (A) Key formulas from the geometric model that was used to predict the architectural properties of skeletal muscle [108]. (B) Illustration of how a 16% decrease in the fiber length and/or a 61% decrease in the fiber CSA would exhibit different effects on the number of muscle fibers that appear in a mid-belly cross-section of the soleus and the plantaris muscles. Note: these are high-resolution images, and details at the single fiber level should be visible when zooming in. Also note that the potential site of cross-section by Booth and Kelso (1973) has been highlighted [151]. (C) Quantitative results from the illustrations in (B), where the data for the control muscles was derived from previously reported architectural properties [84,127,128,143,155,156,157], and the rationale for the 16% decrease in the fiber length and the 61% decrease in the fiber CSA being derived from the average decrease in these values that were reported in the following studies [81,82,84,127,128,143]. (D) Illustration of how a 16% decrease in fiber length and/or a 61% decrease in fiber CSA have no impact on the number of fibers that appear in mid-belly cross-sections (hatched boxes in (B)) of the soleus muscle, but the same changes in fiber length and/or fiber CSA dramatically alter the number of fibers that appear in mid-belly cross-sections of the plantaris.
Figure 5
Figure 5
Representations of CCLs and segmental necrosis. (A) Cross-section of soleus muscle fibers from rats subjected to 12 days of hindlimb suspension. The black arrow points to a conventional CCL, and the white arrow points to a fiber with patches of CCL-like disruptions; copied with permission from [165]. (B,C) Cross-sections and longitudinal-sections of the soleus muscle of a rabbit subjected to 7 days of hindlimb suspension, respectively. The white arrows point to patches of CCL-like disruptions found throughout the muscle fiber; copied with permission from [42]. (D) Longitudinal-section of a soleus muscle fiber from a rat 1 day after being subjected to disuse via tenotomy. The black arrow heads point to a large portion of muscle fibers that has undergone segmental necrosis; copied with permission from [169]. (E) Longitudinal-section of soleus muscle fibers from rats subjected to 7 days of immobilization in a shortened position. The black arrow refers to an area of segmental necrosis near the muscle-tendon junction; copied with permission from [167]. Scale bar = 10 µm in all images.
Figure 6
Figure 6
Illustration of how radial atrophy of myofibrils and/or myofibril hypoplasia can contribute to the radial atrophy of the muscle fibers. The figure is adapted from Jorgenson et al., 2020 [32].
Figure 7
Figure 7
Representations of the moth-eaten appearance of myofibrils that occurs during disuse. Electron micrographs from rat soleus muscles that have been subjected to 7 days of a control condition (A), or 7 days of spaceflight (B). Red arrows point to the presence of gaps in the myofilaments around the periphery of the myofibrils. Black arrows point to the focal loss of myofilaments within the myofibrils. Scale bar = 0.5 µm; copied with permission from [174].
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