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A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation.
- Source :
-
Cell death & disease [Cell Death Dis] 2019 Jul 11; Vol. 10 (7), pp. 528. Date of Electronic Publication: 2019 Jul 11. - Publication Year :
- 2019
-
Abstract
- Micropeptides belong to a class of newly identified small molecules with <100 amino acids in length, and their functions remain largely unknown. Here, we identified a novel muscle-enriched micropeptide that was localized to mitochondria (named MPM, micropeptide in mitochondria) and upregulated during in vitro differentiation of C2C12 myoblasts and in vivo early postnatal skeletal muscle development, and muscle regeneration after cardiotoxin (CTX) damage. Downregulation of MPM was observed in the muscular tissues of tibial muscular dystrophy and Duchenne muscular dystrophy patients. Furthermore, MPM silencing inhibited the differentiation of C2C12 myoblasts into myotubes, whereas MPM overexpression stimulated it. MPM <superscript>-/-</superscript> mice exhibited smaller skeletal muscle fibers and worse muscle performance, such as decrease in the maximum grip force of limbs, the latency to fall off rotarod, and the exhausting swimming time. Muscle regeneration was also impaired in MPM <superscript>-/-</superscript> mice, as evidenced by lower expression of Pax7, MyoD, and MyoG after CTX injection and smaller regenerated myofibers, compared with wild-type mice. Mechanistical investigations based on both gain- and loss-of function studies revealed that MPM increased oxygen consumption and ATP production of mitochondria. Moreover, ectopic expression of PGC-1α, which can enhance mitochondrial respiration, attenuated the inhibitory effect of siMPM on myogenic differentiation. These results imply that MPM may promote myogenic differentiation and muscle fiber growth by enhancing mitochondrial respiratory activity, which highlights the importance of micropeptides in the elaborate regulatory network of both myogenesis and mitochondrial activity and implicates MPM as a potential target for muscular dystrophy therapy.
- Subjects :
- Animals
Cell Differentiation drug effects
Cell Differentiation genetics
Cell Line
Cell Respiration drug effects
Cell Respiration genetics
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Mitochondria genetics
Muscle Fibers, Skeletal metabolism
Muscular Dystrophies genetics
Muscular Dystrophies metabolism
MyoD Protein metabolism
Myoblasts, Skeletal drug effects
Myogenin metabolism
PAX7 Transcription Factor metabolism
Peptides genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
Regeneration genetics
Regeneration physiology
Mitochondria metabolism
Muscle Development drug effects
Muscle Development genetics
Muscle Development physiology
Myoblasts, Skeletal metabolism
Peptides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 31296841
- Full Text :
- https://doi.org/10.1038/s41419-019-1767-y