Going nuclear: Molecular adaptations to exercise mediated by myonuclei

Koopmans, Pieter J.; Zwetsloot, Kevin A.; Murach, Kevin A.

doi:10.1016/j.smhs.2022.11.005

Cited by 5 publications

(5 citation statements)

References 119 publications

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“…Myofibers contain in fact hundreds to thousands of myonuclei which are responsible for ongoing transcription of muscle-specific genes coding for contractile elements, extracellular matrix components, and subunits of the mitochondrial oxidative phosphorylation system. 44 The defective mitochondrial function in muscle, which is not detectable in fibroblasts, supports the notion of an increased demand for transcriptional and translational activities in muscle tissue, which is contingent upon maintaining adequate levels of nucleocytoplasmic Fe-S enzymes. Interestingly, the enlarged mitochondria were observed mainly in type 1 myofibers (Figure 2F, type 1 = darker myofibers), which are known to be rich in mitochondria and to rely on aerobic metabolism, further supporting the idea of a cell specific threshold requirement of the CIA machinery for proper function.…”

Section: Discussionmentioning

confidence: 82%

Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes

Maio,

Orbach,

Zaharieva

et al. 2023

Preprint

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Cytoplasmic and nuclear iron-sulfur enzymes that are essential for genome maintenance and replication depend on the cytoplasmic iron-sulfur assembly (CIA) machinery for cluster acquisition. Here we report that patients with biallelic loss of function inCIAO1, a key CIA component, develop proximal and axial muscle weakness, fluctuating creatine kinase elevation and respiratory insufficiency. In addition, they present with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, macrocytic anemia and gastrointestinal symptoms. Mutational analysis and functional assays revealed reduced stability of the variants compared to wild-type CIAO1. Loss of CIAO1 impaired DNA helicases, polymerases and repair enzymes which rely on the CIA complex to acquire their Fe-S cofactors, with lentiviral restoration reversing all patient-derived cellular abnormalities. Our study identifiesCIAO1as a novel human disease gene and provides insights into the broader implications of the iron-sulfur assembly pathway in human health and disease.

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Section: Discussionmentioning

confidence: 82%

Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes

Maio,

Orbach,

Zaharieva

et al. 2023

Preprint

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show abstract

“…Sufficient levels of those enzymes are critical to meet the cellular needs for transcriptional and translational activities. Therefore, this impairment becomes particularly notable in muscle tissue, known for its high protein turnover rates ( 39 ). Interestingly, we observed the enlarged mitochondria mainly in type 1 myofibers ( Figure 2F , type 1 = darker myofibers), which are known to be rich in mitochondria and to rely on aerobic metabolism, further supporting the idea of a cell-specific threshold requirement of the CIA machinery for proper function.…”

Section: Discussionmentioning

confidence: 99%

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes

Maio,

Orbach,

Zaharieva

et al. 2024

Journal of Clinical Investigation

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“…The intracellular signaling pathways activated by exercise regulate numerous cellular functions, including protein synthesis and degradation, ion balance, energy metabolism, and transcriptional regulation [31]. Cellular adaptations induced by exercise, such as changes in muscle capillary density, mitochondrial homeostasis, satellite cells, and myonuclei, are complex and multi-dimensional [32]. Endurance training, such as long-distance running or cycling, can affect the composition of muscle fiber types.…”

Section: Discussionmentioning

confidence: 99%

Endurance Exercise-Induced Fgf21 Promotes Skeletal Muscle Fiber Conversion through TGF-β1 and p38 MAPK Signaling Pathway

Luo

Zhang

Cao

et al. 2023

IJMS

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Fgf21 has been identified as playing a regulatory role in muscle growth and function. Although the mechanisms through which endurance training regulates skeletal muscle have been widely studied, the contribution of Fgf21 remains poorly understood. Here, muscle size and function were measured, and markers of fiber type were evaluated using immunohistochemistry, immunoblots, or qPCR in endurance-exercise-trained wild-type and Fgf21 KO mice. We also investigated Fgf21-induced fiber conversion in C2C12 cells, which were incubated with lentivirus and/or pathway inhibitors. We found that endurance exercise training enhanced the Fgf21 levels of liver and GAS muscle and exercise capacity and decreased the distribution of skeletal muscle fiber size, and fast-twitch fibers were observed converting to slow-twitch fibers in the GAS muscle of mice. Fgf21 promoted the markers of fiber-type transition and eMyHC-positive myotubes by inhibiting the TGF-β1 signaling axis and activating the p38 MAPK signaling pathway without apparent crosstalk. Our findings suggest that the transformation and function of skeletal muscle fiber types in response to endurance training could be mediated by Fgf21 and its downstream signaling pathways. Our results illuminate the mechanisms of Fgf21 in endurance-exercise-induced fiber-type conversion and suggest a potential use of Fgf21 in improving muscle health and combating fatigue.

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Going nuclear: Molecular adaptations to exercise mediated by myonuclei

Cited by 5 publications

References 119 publications

Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes

Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes

Endurance Exercise-Induced Fgf21 Promotes Skeletal Muscle Fiber Conversion through TGF-β1 and p38 MAPK Signaling Pathway

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