Inhibition of mitochondrial and cytosolic calpain attenuates atrophy in myotubes co‑cultured with colon carcinoma cells

Zeng, Xianliang; Zhao, Li; Chen, Sizeng; Li, Xiantao

doi:10.3892/ol.2020.12385

Cited by 4 publications

(5 citation statements)

References 41 publications

(63 reference statements)

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“…The most straightforward technical approach involves the isolation of mitochondria, thereby removing the nuclei, and hence, the nuclear genome and NUMTs, from the sample [38,39]. Mitochondrial isolation can be achieved with relative ease in cell pellets or whole animal or human tissue through the use of commercially available kits [40][41][42]. Differential centrifugation techniques employed by these kits result in minimal nuclear contamination, which would not be expected to contribute a sufficient number of reads during next-generation sequencing to be problematic in heteroplasmic mtDNA variant detection (Figure 1).…”

Section: Technical Approaches For Limiting Numtsmentioning

confidence: 99%

The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome

et al. 2023

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Nuclear-mitochondrial DNA segments (NUMTs) are mitochondrial DNA (mtDNA) fragments that have been inserted into the nuclear genome. Some NUMTs are common within the human population but most NUMTs are rare and specific to individuals. NUMTs range in size from 24 base pairs to encompassing nearly the entire mtDNA and are found throughout the nuclear genome. Emerging evidence suggests that the formation of NUMTs is an ongoing process in humans. NUMTs contaminate sequencing results of the mtDNA by introducing false positive variants, particularly heteroplasmic variants present at a low variant allele frequency (VAF). In our review, we discuss the prevalence of NUMTs in the human population, the potential mechanisms of de novo NUMT insertion via DNA repair mechanisms, and provide an overview of the existing approaches for minimizing NUMT contamination. Apart from filtering known NUMTs, both wet lab-based and computational methods can be used to minimize the contamination of NUMTs in analyses of human mtDNA. Current approaches include: (1) isolating mitochondria to enrich for mtDNA; (2) applying basic local alignment to identify NUMTs for subsequent filtering; (3) bioinformatic pipelines for NUMT detection; (4) k-mer-based NUMT detection; and (5) filtering candidate false positive variants by mtDNA copy number, VAF, or sequence quality score. Multiple approaches must be applied in order to effectively identify NUMTs in samples. Although next-generation sequencing is revolutionizing our understanding of heteroplasmic mtDNA, it also raises new challenges with the high prevalence and individual-specific NUMTs that need to be handled with care in studies of mitochondrial genetics.

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Section: Technical Approaches For Limiting Numtsmentioning

confidence: 99%

The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome

et al. 2023

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“…Coculture of myoblasts with colon carcinoma cells activates calpains in myotube mitochondria causing non-selective pore opening on the inner membrane of mitochondria (MPTP) and mitochondrial membrane potential (Δψ m ) alterations, together resulting in mitochondrial injury. Furthermore, mitochondrial respiration becomes altered by an impaired OXPHOS complex I activity in myotube mitochondria [ 56 ]. Additionally, they showed that inhibition of calpain improves the function of OXPHOS complex I and thus mitochondrial respiration [ 56 ].…”

Section: Underlying Mechanisms Of Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Furthermore, mitochondrial respiration becomes altered by an impaired OXPHOS complex I activity in myotube mitochondria [ 56 ]. Additionally, they showed that inhibition of calpain improves the function of OXPHOS complex I and thus mitochondrial respiration [ 56 ]. This could implicate that there is upregulated activation of the calpain system in CRC related cachexia mouse models, contributing to muscle atrophy.…”

Section: Underlying Mechanisms Of Mitochondrial Dysfunctionmentioning

confidence: 99%

The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?

Haterd

Verboven

Vandenabeele

et al. 2022

IJMS

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Up to 60% of colorectal cancer (CRC) patients develop cachexia. The presence of CRC related cachexia is associated with more adverse events during systemic therapy, leading to a high mortality rate. The main manifestation in CRC related cachexia is the loss of skeletal muscle mass, resulting from an imbalance between skeletal muscle protein synthesis and protein degradation. In CRC related cachexia, systemic inflammation, oxidative stress, and proteolytic systems lead to mitochondrial dysfunction, resulting in an imbalanced skeletal muscle metabolism. Mitochondria fulfill an important function in muscle maintenance. Thus, preservation of the skeletal muscle mitochondrial homeostasis may contribute to prevent the loss of muscle mass. However, it remains elusive whether mitochondria play a benign or malignant role in the development of cancer cachexia. This review summarizes current (mostly preclinical) evidence about the role of skeletal muscle mitochondria in the development of CRC related cachexia. Future human research is necessary to determine the physiological role of skeletal muscle mitochondria in the development of human CRC related cachexia.

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Section: Calcium-activated Protease Calpainsmentioning

confidence: 99%

“…The muscle wasting observed in cachexia is associated with several proteolytic pathways and processes, including the calpain system [54]. These proteins are associated with the initiation of protein breakdown during cachexia since calpain-dependent cleavage of myofilaments is considered the initial step in muscle proteolysis [54,55]. Calpains comprise a family of calcium-activated cysteine proteases, which cleave at exposed regions between domains of proteins affecting muscle in synergisms with UPP [55,56].…”

Section: Calcium-activated Protease Calpainsmentioning

confidence: 99%

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

et al. 2021

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As a multifactorial and multiorgan syndrome, cancer cachexia is associated with decreased tolerance to antitumor treatments and increased morbidity and mortality rates. The current approaches for the treatment of this syndrome are not always effective and well established. Drug repurposing or repositioning consists of the investigation of pharmacological components that are already available or in clinical trials for certain diseases and explores if they can be used for new indications. Its advantages comparing to de novo drugs development are the reduced amount of time spent and costs. In this paper, we selected drugs already available or in clinical trials for non-cachexia indications and that are related to the pathways and molecular components involved in the different phenotypes of cancer cachexia syndrome. Thus, we introduce known drugs as possible candidates for drug repurposing in the treatment of cancer-induced cachexia.

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Inhibition of mitochondrial and cytosolic calpain attenuates atrophy in myotubes co‑cultured with colon carcinoma cells

Cited by 4 publications

References 41 publications

The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome

The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome

The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

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