Universität zu Köln

Baraldo, Martina, Geremia, Alessia, Pirazzini, Marco ORCID: 0000-0003-4127-254X, Nogara, Leonardo, Solagna, Francesca, Tuerk, Clara, Nolte, Hendrik, Romanello, Vanina, Megighian, Aram, Boncompagni, Simona, Kruger, Marcus, Sandri, Marco and Blaauw, Bert (2020). Skeletal muscle mTORC1 regulates neuromuscular junction stability. J. Cachexia Sarcopenia Muscle, 11 (1). S. 208 - 226. HOBOKEN: WILEY. ISSN 2190-6009

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Abstract

Background Skeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined. Methods Inducible, muscle-specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force. Results We found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle-specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3-8% of NCAM-positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat-beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM-positive fibres in Raptor k.o. muscles. Conclusions Our study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well-established activation of mTORC1 in skeletal muscle during and after exercise.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Baraldo, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Geremia, Alessia UNSPECIFIED UNSPECIFIED UNSPECIFIED Pirazzini, Marco UNSPECIFIED orcid.org/0000-0003-4127-254X UNSPECIFIED Nogara, Leonardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Solagna, Francesca UNSPECIFIED UNSPECIFIED UNSPECIFIED Tuerk, Clara UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Romanello, Vanina UNSPECIFIED UNSPECIFIED UNSPECIFIED Megighian, Aram UNSPECIFIED UNSPECIFIED UNSPECIFIED Boncompagni, Simona UNSPECIFIED UNSPECIFIED UNSPECIFIED Kruger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Sandri, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaauw, Bert UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-130398
DOI:	10.1002/jcsm.12496
Journal or Publication Title:	J. Cachexia Sarcopenia Muscle
Volume:	11
Number:	1
Page Range:	S. 208 - 226
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2190-6009
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TARGETED SOMATIC MUTAGENESIS; MOUSE MODEL; AUTOPHAGY; RAPAMYCIN; DEGENERATION; ACTIVATION; HOMEOSTASIS; PROGRESSION; SYNAPSES; PROTECTS Multiple languages Geriatrics & Gerontology; Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13039