Fibroblast growth factor 2-stimulated proliferation is lower in muscle precursor cells from old rats.
In aged skeletal muscle, impairments in regrowth and regeneration may be explained by a decreased responsiveness of muscle precursor cells (MPCs) to environmental cues such as growth factors. We hypothesized that impaired responsiveness to fibroblast growth factor 2 (FGF2) in MPCs from old animals would be explained by impaired FGF2 signalling. We determined that 5-bromo-2'-deoxyuridine (BrdU) incorporation and cell number increase less in MPCs from 32- compared with 3-month-old rats. In the presence of FGF2, we demonstrated that there were age-associated differential expression patterns for FGF receptor 1 and 2 mRNAs. Measurement of downstream signalling revealed that that mitogen-activated protein kinase/ERK kinase 1/2 (MEK1/2)-extracellular signal-regulated kinase 1/2, protein kinase C and p38 were FGF2-driven pathways in MPCs. Uniquely, protein kinase C signalling was shown to play the largest role in FGF2-stimulated proliferation in MPCs. c-Jun N-terminal kinase (JNK) signalling was ruled out as an FGF2-stimulated proliferation pathway in MPCs. Inhibition of JNK had no effect on FGF2 signalling to BrdU incorporation, and FGF2 treatment was associated with increased phosphorylation of p38, which inhibits, rather than stimulates, BrdU incorporation in MPCs. Surprisingly, the commonly used vehicle, dimethyl sulphoxide, rescued proliferation in MPCs from old animals. These findings provide insight for the development of effective treatment strategies that target the age-related impairments of MPC proliferation in old skeletal muscle.
Jump
Seth S
SS
Department of Biomedical Science, University of Missouri-Columbia, Columbia, MO 65211, USA.
Childs
Tom E
TE
Zwetsloot
Kevin A
KA
Booth
Frank W
FW
Lees
Simon J
SJ
D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; C496350:Fgfr1 protein, rat; C496356:Fgfr2 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine