Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short‐term disuse in healthy younger humans Academic Article uri icon

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abstract

  • Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3 mL.kg-1 ), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.

authors

  • Willis, Craig RG
  • Gallagher, Iain J
  • Wilkinson, Daniel J
  • Brook, Matthew S
  • Bass, Joseph J
  • Phillips, Bethan E
  • Smith, Kenneth
  • Etheridge, Timothy
  • Stokes, Tanner
  • McGlory, Chris
  • Gorissen, Stefan HM
  • Szewczyk, Nathaniel J
  • Phillips, Stuart
  • Atherton, Philip J

publication date

  • September 2021