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L-type Ca2+ channel-insulin-like growth factor-1 receptor signaling impairment in aging rat skeletal muscle
M Renganathan1, W E Sonntag, O Delbono
1Department of Internal Medicine and Gerontology, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA. mrengana@bgsm.edu
Abstract:
The present study investigates the modulation of skeletal muscle L-type Ca2+ channel receptor in response to insulin-like growth factor-1 receptor (IGF-1R) activation. Single extensor digitorum longus and multifiber preparations were isolated from 7- (young), 14- (middle-age) and 28-(old) month- Fisher 344 X Brown Norway rats. Calcium current was potentiated in fibers from young and middle-age rats due to a -13 mV shift in half-activation potential. Fibers from old animals failed to show current potentiation in response to IGF-1R activation. IGF-1 induced a ten-fold increase in the phosphorylation of the L-type Ca2+ channel alpha1 subunit in young and middle-age fibers but failed to induce phosphorylation in old fibers. Addition of 0.5 mM Ca2+ increased the IGF-1 induced phosphorylation in young and middle-age fibers three fold but not in old fibers. The tyrosine kinase inhibitor, genistein, and the PKC inhibitor peptide, 19-36, decreased IGF-1 induced phosphorylation of alpha1 subunit to 15% in young and middle-age fibers but failed to inhibit phosphorylation in old fibers. These results demonstrate that the IGF-1-L-type Ca2+ channel alpha1 subunit signaling is impaired in skeletal muscle fibers from old animals due to alterations in the trk-PKC pathway.
Insights
Aging impairs insulin-like growth factor-1 receptor (IGF-1R) signaling in skeletal muscle, affecting L-type Ca2+ channel function. This age-related decline in IGF-1R modulation of calcium channels is linked to the trk-PKC pathway.
Area of Science:
- Physiology
- Molecular Biology
- Aging Research
Background:
- Skeletal muscle function relies on L-type Ca2+ channels.
- Insulin-like growth factor-1 receptor (IGF-1R) plays a role in muscle physiology.
- Age-related changes can impact cellular signaling pathways.
Purpose of the Study:
- To investigate how IGF-1R activation modulates L-type Ca2+ channels in rat skeletal muscle across different age groups.
- To identify age-dependent differences in IGF-1R signaling pathways affecting calcium channels.
Main Methods:
- Isolation of extensor digitorum longus and multifiber skeletal muscle preparations from young, middle-aged, and old rats.
- Measurement of calcium current potentiation and L-type Ca2+ channel alpha1 subunit phosphorylation in response to IGF-1.
- Assessment of the effects of calcium concentration and specific inhibitors (genistein, 19-36) on IGF-1 induced phosphorylation.
Main Results:
- IGF-1R activation potentiated calcium current and increased alpha1 subunit phosphorylation in young and middle-aged rats, but not in old rats.
- Calcium addition enhanced IGF-1 induced phosphorylation in younger animals but not in older ones.
- Tyrosine kinase and PKC inhibitors blocked IGF-1 induced phosphorylation in young/middle-aged fibers but were ineffective in old fibers.
Conclusions:
- The IGF-1R signaling pathway, which modulates L-type Ca2+ channel alpha1 subunit, is impaired in skeletal muscle of old rats.
- Alterations in the trk-PKC pathway contribute to the age-related deficit in IGF-1R-mediated calcium channel modulation.