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age-associated changes in skeletal muscle

Skeletal muscle undergoes change with aging. Physiology: 1) age-associated changes occur in skeletal muscle, tendons, bursae, connective tissue & nerves [8] 2) sarcopenia a) responsive to training b) parallels decrease in basal metabolic rate c) muscle tissue may be replaced with fibrous tissue d) loss in muscle strength exceeds loss in muscle mass - loss least in diaphragm - loss > in legs than arms e) rate of skeletal mass loss with age may he independent of level of physical activity - exercise increases baseline muscle mass, but may not mitigate its rate of loss with age [8,12] 3) increased fatigability 4) small increase in number of slow-twitch (type 1) fibers 5) loss of fast-twitch (type 2) fibers a) slower musccle contraction b) lower peak strength of muscle contraction c) slower muscle relaxation [8] 6) reduction in the number of motor units & fibers/unit 7) infiltration of fat & lipofuscin into muscle bundles 8) decreased myosin heavy chain synthesis 9) adult skeletal muscle regenerates throughout life, but as the muscle ages, its ability to repair diminishes & eventually fails 10) skeletal muscle cells are more likely to undergo apoptosis in response to physical inactivity [8] 11) impairment is associated with an increase in tissue fibrosis 12) age-related muscle stem cell dysfunction - type 2 muscle fiber stem cells (MF2SC) from older humans contain higher levels of myostatin after exercise than MF2SC from younger individuals (& perhaps before exercise as well) [9] 13) a balance between endogenous pSmad3 & active Notch controls regenerative capacity of muscle stem cells; deregulation of this balance in old muscle interferes with regeneration [5] 14) Notch expression declines in old muscle & old muscle produces excessive TGF-beta (but not myostatin) 15) TGF-beta induces Smad3 via TGFBR1 16) endogenous Notch & Smad3 antagonize each other in control of satellite-cell proliferation a) activation of Notch blocks the TGF-beta-dependent upregulation of cyclin-dependent kinase inhibitors (CDKI) CDKN1A, CDKN1B, CDKN2A & CDKN2B b) whereas inhibition of Notch induces them c) in muscle stem cells, Notch activity determines binding of pSmad3 to promoters of CDKI genes CDKN1A, CDKN1B, CDKN2A & CDKN2B 17) attenuation of TGF-beta/pSmad3 in old, injured muscle restores regeneration to satellite cells in vivo 18) cyclic inhibition of STAT3 recruits muscle stem cells & promotes muscle repair [15] - STAT3 activates transcription of genes in response to IL-6 19) alterations in FGFR1 & p38-MAP kinase signaling affect age-related muscle stem cell dysfunction [10] Radiology: - clinical relevance of abnormal imaging in the elderly is often unclear Management: - diet & exercise programs may improve skeletal muscle function in the elderly (see sarcopenia) Comparative biology: 1) age-related muscle stem cell dysfunction a) muscle stem cells (satellite cells) from aged mice tend to convert from a myogenic to a fibrogenic lineage as they begin to proliferate & this conversion is mediated by factors in the systemic environment of the old animals via Wnt signaling [6] a) p16ink4A silencing by RNA interference restores regenerative capacity of satellite cells in old mice [11] 2) heterochronic parabioses, exposing old mice to factors present in young serum restores activation of Notch signalling & regenerative capacity of aged satellite cells [7] 3) muscle transplantation studies in rats demonstrated that poor regeneration of muscles in old animals is a function of the host environment rather than an intrinsic defect in the host muscle stem cells [13] 4) blood of young mice contains substances that reverse aging processes in heart muscle, skeletal muscle, & brain - one of these substances is GDF11 [14] 5) PGE2 stimulates muscle stem cells & helps repair muscle damage [16] - during aging, activity of 15-PGDH that degrades PGE2 progressively increases in muscle macrophages - inhibiting macrophage 15-PGDH activity in older mice, by either genetic or pharmacologic interventions, raises levels of PGE2 & restores aged muscle, functionally & anatomically similar to muscle of young mice [16]

Related

circulating plasma factors in cellular senescence muscular disease; myopathy sarcopenia skeletal muscle (voluntary muscle)

General

age-related physiological changes

References

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  14. Sinha M et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014 May 9; 344:649. PMID: 24797481
  15. Tierney MT, Aydogdu T, Sala D et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat Med. 2014. Oct;20(10):1182-6 PMID: 25194572 PMCID: PMC4332844 Free PMC article
  16. Palla AR, Ravichandran M, Wang YX et al. Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science 2021 Jan 29; 371:eabc8059 PMID: 33303683 https://science.sciencemag.org/content/371/6528/eabc8059