Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse

Iqbal, Sobia; Ostojić, Olga; Singh, Kuldeep; Joseph, Anna‐Maria; Hood, David A.

doi:10.1002/mus.23838

Cited by 140 publications

(133 citation statements)

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“…Oxidative stress is relevant to the pathophysiology of numerous diseases, including the aging process, since it can damage DNA, proteins, and lipids (2), and plays a key role in age-related tissue dysfunction. During aging, an increased incidence of mitochondrial fragmentation has been observed, with a concomitant increase in the expression of mitochondrial fission proteins (19). Our data suggest that enhanced oxidative stress may underlie the mitochondrial dysfunction and fragmentation observed during the aging process.…”

Section: Discussionmentioning

confidence: 52%

“…In addition, Chen et al (10) reported that impaired mitochondrial fusion as a result of mitofusin 1/2 or optic atrophy 1 deficiency resulted in lower rates of respiration (10), resembling the effects found in our H 2 O 2 -treated cells. Fragmented mitochondrial structures have been observed by others using similar stressful indicators (14,16,19,20,23). The resulting fragmented organelles allow for the damaged portions of the mitochondrial network to be isolated from its unaffected parts.…”

Section: Discussionmentioning

confidence: 68%

“…Within these organelles, low levels of ROS are constantly produced during normal respiration when the O 2 consumed undergoes a one-electron reduction. In skeletal muscle subject to conditions of chronic muscle disuse (1) and aging (8), increased production of ROS from mitochondria occurs, and this coincides with an increased incidence of mitochondrial fragmentation (19). More direct connections between oxidative stress and mitochondrial morphology have previously been shown in endothelial cells and neurons and, recently, in C 2 C 12 cells, whereby exposure to high levels of H 2 O 2 , a major contributor to oxidative stress, induces mitochondrial fragmentation (3,5,21).…”

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confidence: 99%

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Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts

Iqbal

Hood

2014

American Journal of Physiology-Cell Physiology

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Iqbal S, Hood DA. Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts. Am J Physiol Cell Physiol 306: C1176 -C1183, 2014. First published April 16, 2014; doi:10.1152/ajpcell.00017.2014.-Mitochondria are dynamic organelles, capable of altering their morphology and function. However, the mechanisms governing these changes have not been fully elucidated, particularly in muscle cells. We demonstrated that oxidative stress with H2O2 resulted in a 41% increase in fragmentation of the mitochondrial reticulum in myoblasts within 3 h of exposure, an effect that was preceded by a reduction in membrane potential. Using live cell imaging, we monitored mitochondrial motility and found that oxidative stress resulted in a 30% reduction in the average velocity of mitochondria. This was accompanied by parallel reductions in both organelle fission and fusion. The attenuation in mitochondrial movement was abolished by the addition of N-acetylcysteine. To investigate whether H2O2-induced fragmentation was mediated by dynaminrelated protein 1, we incubated cells with mDivi1, an inhibitor of dynamin-related protein 1 translocation to mitochondria. mDivi1 attenuated oxidative stress-induced mitochondrial fragmentation by 27%. Moreover, we demonstrated that exposure to H2O2 upregulated endoplasmic reticulum-unfolded protein response markers before the initiation of mitophagy signaling and the mitochondrial-unfolded protein response. These findings indicate that oxidative stress is a vital signaling mechanism in the regulation of mitochondrial morphology and motility. mitochondria; mitochondrial movement; oxidative stress; mitochondrial morphology MITOCHONDRIA ARE ESSENTIAL ORGANELLES for the life and death of eukaryotic cells. They play key roles in aerobic energy production, apoptosis, mitophagy, and cellular signaling. These versatile organelles were once thought to be static and rigid structures. More recently, mitochondria have been appreciated for their dynamic nature. They can change their distribution by moving along cytoskeletal tracks or change their overall morphology. The maintenance and appropriate networking of mitochondria within the cell is mediated by fusion and opposing fission processes. Fusion involves the mixing of mitochondrial material, whereas fission divides the organelle into smaller components. Disruptions in either of these opposing events can lead to developmental defects and disease (29), suggesting that the proper maintenance of mitochondrial morphology is critical for normal cell function.Mitochondrial fission is orchestrated, in part, by dynaminrelated protein 1 (Drp1) (4, 25), a protein that is a GTPase of the dynamin family. All dynamin members are structurally similar but functionally diverse GTP-binding proteins. Drp1 assists in mitochondrial fission by polymerizing into a ring-like structure around the organelle. The cross-bridging of the GTPase domains of adjacent Drp1 proteins results in GTP hydrolysis, constriction, and the ultimate severing of mitochon...

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 68%

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confidence: 99%

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Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts

Iqbal

Hood

2014

American Journal of Physiology-Cell Physiology

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“…This includes evidence of the presence of small, fragmented mitochondria compared with that found in young muscle (68,102), as well as occasional instances of giant mitochondria (10,116). This puzzling combination forces us to consider the ratio of the expression of fusion and fission regulatory proteins that govern mitochondrial morphology.…”

Section: Morphology and Agingmentioning

confidence: 99%

“…Based on this, it appears that the rate of mitochondrial dynamics (i.e., fusion and fission) is suppressed in sarcopenic rat muscle, since transcript and protein expression of Drp1, Fis1, Mfn1, Mfn2, and Opa1 were reduced (66). Although some variability exists between studies, other reports from muscle of aged rodents and humans have observed that the balance of these regulatory factors is skewed toward favoring greater rates of fission, compared with fusion, within aged muscle (68,73,177). This appears to coincide with the preponderance of data that document a more fragmented organelle phenotype in muscle with age (FIGURE 3).…”

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Mitochondria, Muscle Health, and Exercise with Advancing Age

2015

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Skeletal muscle health is dependent on the optimal function of its mitochondria. With advancing age, decrements in numerous mitochondrial variables are evident in muscle. Part of this decline is due to reduced physical activity, whereas the remainder appears to be attributed to age-related alterations in mitochondrial synthesis and degradation. Exercise is an important strategy to stimulate mitochondrial adaptations in older individuals to foster improvements in muscle function and quality of life.Heather N. Carter, Chris C. W. The process of aging exploits the malleable nature of skeletal muscle. The age-related loss of muscle mass was termed sarcopenia, based on the Greek (sarx, flesh) and (penia, poverty) in 1988 (139). Accompanying this loss are profound architectural and molecular changes that alter muscle quality and are manifested in functional limitations. Decreases in muscle fiber number as well as fiber cross-sectional area are both contributing factors to sarcopenia (92) and consequently adversely affect force production (strength) (46, 63) and endurance of the older individual (12). Muscle mass typically peaks in the mid-20s (12, 34,92), and thereafter several distinct phases of muscle loss have been identified. In the third to fifth decade of life, a slow rate of muscle mass loss is noted, amounting to ϳ10% in total (34,92). In later adulthood (Ͼ45 yr), the rate of muscle loss increases, with appraisals ranging between 0.5 and 1.4% per year (12, 34,69). Even more dramatic changes are noted beyond the sixth decade of life. Along with the functional impairments imposed by sarcopenia, are the associated escalations in health care costs, along with coincident rises in metabolic diseases (e.g., Type 2 diabetes, obesity) and a greater risk of falls (67). In the U.S., it is expected that those 65 years of age and over will comprise ϳ20% of the population, or ϳ72 million people, by the year 2030 (20). Since the proportion of older adults is increasing, continued research into the mechanisms of muscle loss is warranted, along with the investigation of therapeutic strategies that can mitigate muscle atrophy during aging. Mitochondria have been implicated as potential mediators of sarcopenia. Recently, it has been suggested that dysfunction of these organelles can be considered a feature of aging (105). However, considerable controversy exists regarding the extent to which muscle mitochondria may be dysfunctional with aging, and thereby contribute to the loss of this tissue. Thus the purpose of this review is to examine the literature with respect to mitochondrial content and function in muscle with advancing age, and provide a perspective on the effectiveness of endurance/aerobic exercise as an intervention for mitochondrial biogenesis and muscle homeostasis in older individuals. Structural Features of Muscle Relevant to SarcopeniaIn young, healthy individuals, skeletal muscle comprises ϳ40% of total body mass and is important for locomotion and whole body metabolism. Myosin ATPase histochemistry and electrop...

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The Role of Mitochondria in Age‐Related Sarcopenia

et al. 2021

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Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse

Abstract: Chronic muscle use increases the ratio of fusion:fission proteins, leading to reticular mitochondria, whereas muscle disuse and aging result in a decrease in this ratio, culminating in fragmented organelles.

Cited by 140 publications

References 42 publications

Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts

Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts

Mitochondria, Muscle Health, and Exercise with Advancing Age

The Role of Mitochondria in Age‐Related Sarcopenia

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