Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition

This 2020 Aging paper from a New Zealand–USC collaboration (the Cameron-Smith and Cohen groups) is the most rigorous published human-cohort characterisation of MOTS-c across age strata in skeletal muscle and plasma simultaneously. The investigators enrolled 104 healthy men in three age groups — young (18–30 years), middle-aged (45–55 years), and older (70–81 years) — and measured circulating plasma MOTS-c, skeletal-muscle MOTS-c expression (vastus lateralis biopsies), and a panel of muscle-quality and fibre-composition markers. Plasma MOTS-c showed the expected age-decline pattern — middle-aged and older cohorts had 11% and 21% lower circulating MOTS-c respectively than the young group, consistent with the Lee 2015 framing of declining mitochondrial-peptide signalling with age. Strikingly, skeletal-muscle MOTS-c expression moved in the opposite direction — older and middle-aged men had approximately 1.5-fold higher muscle MOTS-c expression than young men. The muscle-tissue MOTS-c correlated with slow-fibre composition (consistent with the age-associated fast-to-slow fibre-type shift) and, in the older group, with muscle quality measured as leg-press strength normalised to thigh cross-sectional area. The paper demonstrates that the simple "MOTS-c declines with age" framing is incomplete and that tissue-specific regulation is more complex than the plasma pattern alone would suggest.