søndag den 25. september 2016

Is autophagy dysregulated in ME?

Autophagy is a process that provides the degradation of damaged cellular components.

The activation of autophagy during physical activity in muscle cells is necessary for maintaining tissue homeostasis by preventing the accumulation of damaged mitochondria and myofibril degeneration.

Collagen VI is one of the major skeletal muscle extracellular matrix proteins. Mice without the gene for collagen VI have a block in autophagy leading to the accumulation of damaged mitochondria.

Attempts to induce autophagic flux by subjecting these mutant mice to long-term or shorter bursts of physical activity are unsuccessful. In normal mice, the induction of autophagy in the skeletal muscles post-exercise is able to prevent the accumulation of damaged organelles and maintain cellular homeostasis (ref 1)

Another crucial function of autophagy in development and homeostasis of the immune system is the elimination of autoreactive T cells in the thymus (ref 2)

Autophagy also plays an important role in the survival of cancer cells.

TRPM3 and miR-204 regulate autophagy in clear cell renal carcinoma:

Figure 1.
Robust control of the autophagic network by microRNAs and calcium- and zinc-activated pathways. Calcium and zinc entering the cell through the TRPM3 channel stimulate oncogenic autophagy mediated by LC3A and LC3B through a dual mechanism. Calcium stimulates phagophore initiation through Ca2+-dependent activation of CAMKK2 and AMPK, and the resulting phosphorylation of ULK1. Calcium and zinc also inhibit miR-214, which directly targets LC3A and LC3B. The VHL tumor suppressor inhibits expression of TRPM3 directly and indirectly through the effect of miR-204 on CAV1. In addition, miR-204 directly targets LC3B. AMPK, AMP-activated protein kinase; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2, β; CAV1, caveolin 1; LC3A, microtubule-associated protein 1 light chain 3 α; LC3B, microtubule-associated protein 1 light chain 3 β; TRPM3, transient receptor potential melastatin 3; ULK1, unc-51 like autophagy activating kinase 1; VHL, Von Hippel-Lindau.

TRPM3 and calcium are dysregulated in immune cells from ME patients
Elegant research from Griffith University has shown significant reduction in TRPM3 cell surface expression in NK and B cells, as well as decreased intracellular calcium in ME patients (ref 4)

A study on microRNA in NK cells from ME patients showed reduced expression in genes involved in the autophagy, WNT and AKT signaling pathways (ULK1, ATG2A, PMEPA1, DKK3, PDCD4) (ref 5)

Could TRPM3 be involved in autophagy in immune cells?

And could dysregulated autophagy be involved in exercise intolerance in ME?

  1. Autophagy. 2011 Dec 1; 7(12): 1405-1406. doi: 10.4161/auto.7.12.18315 Activvation of autophagy is required for muscle homeostasis during physical exercise. Usha Nair and Daniel J. Klionsky
  2. Levne et al: Nature: 2011 January 20; 469(7330): 323.325. doi:10.1038/nature09782.
  3. Mol Cell Oncol. 2015 Oct-Dec;2(4):e1002712. Nicolas G Cost and Maria F. Czyzyk-Krzeska http://dx.doi.org/10.1080/23723556.2014.1002712
  4. Petty et al: MicroRNAs: Potential Diagnostic Biomarkers in NK cells of patients with CFS/ME. PLOS ONE. DOI:10.1371/journal.pone.0150904 march 11,2016

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