Insulin-like Growth Factor-1 Increases Skeletal Muscle Dihydropyridine Receptor α1S Transcriptional Activity by Acting on the cAMP-response Element-binding Protein Element of the Promoter Region

Zheng, Zhenlin; Wang, Zhongmin; Delbono, Osvaldo

doi:10.1074/jbc.m210526200

Cited by 26 publications

(31 citation statements)

References 42 publications

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“…2G,H), indicating that TnT3 binds to each independently. TnT3 binding to the Cacna1s promoter region is consistent with our previous report that most transcription factor binding sites are located within 1 kb upstream of the Cacna1s' transcription start site (Zheng et al ., 2002b). …”

Section: Resultsmentioning

confidence: 99%

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Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

et al. 2016

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SummaryLoss of strength in human and animal models of aging can be partially attributed to a well‐recognized decrease in muscle mass; however, starting at middle‐age, the normalized force (force/muscle cross‐sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation–contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full‐length TnT3 (FL‐TnT3) and its carboxyl‐terminal (CT‐TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA‐410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.

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Section: Resultsmentioning

confidence: 99%

“…Our studies indicate that TnT3‐mediated Cacna1 transcription is a primary but not the only mechanism regulation Cav1.1 expression (Zheng et al ., 2002b). Restoring nuclear levels of FL‐TnT3 by calpain inhibition significantly recovers Cav1.1 expression but we do not know how completely.…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

et al. 2016

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“…Accordingly, research is therefore examining roles of IGF-1 replacement or replenishment as potential treatment for age-related disease and degeneration (Groban, et al, 2006,Schmidmaier, et al, 2006,Sonntag, et al, 2005. We and others have previously shown that IGF-1 overexpression in skeletal muscle of aging mice prevents deleterious effects of age on skeletal muscle and the neuromuscular system as a whole (Barton-Davis, et al, 1998,Gonzalez, et al, 2003,Musaro, et al, 2001,Renganathan, et al, 1998,Zheng, et al, 2002. Since gene therapy is possibly far off in the future, transgenic humans are not feasible at this time.…”

Section: Discussionmentioning

confidence: 99%

“…A major contributor to specific force decline in aging muscle is the decrease in DHPRα1 subunit expression (Delbono, et al, 1995,Gonzalez, et al, 2000,Gonzalez, et al, 2003,Wang, et al, 2000; and IGF-1 overexpression exclusively in skeletal muscle prevents both DHPRα1 subunit and specific force decline (Gonzalez, et al, 2003,Renganathan, et al, 1998,Wang, et al, 1999,Zheng, et al, 2002. We have recently reported that IGF-1 targeted to motor neurons with hIGF-1-TTC injections increased specific force of single intact EDL fibers from aged mice (Payne, et al, 2006).…”

Section: Igf-1 Targeted To Motor Neurons Increases Dhprα1 Subunit Promentioning

confidence: 99%

“…Muscle IGF-1 overexpression prevents several deleterious effects of aging, including muscle mass and specific force decline (Barton-Davis, et al, 1998,Gonzalez, et al, 2003. The site of action for the effects of elevated muscle IGF-1 has been postulated to be: 1) the muscle itself, increasing DHPR expression and function through IGF-1 receptor signaling (Renganathan, et al, 1998,Zheng, et al, 2002, or 2) the motor neuron, via paracrine trophic effects, preserving innervation and thus function of aged muscle fibers (Barton-Davis, et al, 1998,Messi andDelbono, 2003). These data from transgenic mice indicate that elevated IGF-1 prevents this type of contractile deficit in aged muscle fibers, but does not elucidate the site of action of the IGF-1.…”

Section: Igf-1 and External Ca 2+ -Dependent Skeletal Muscle Contractionmentioning

confidence: 99%

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Motor neuron targeting of IGF-1 attenuates age-related external Ca2+-dependent skeletal muscle contraction in senescent mice

Payne

Messi

Zheng

et al. 2007

Experimental Gerontology

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A population of fast muscle fibers from aging mice is dependent on external Ca 2+ to maintain tetanic force during repeated contractions. We hypothesized that age-related denervation in muscle fibers plays a role in initiating this contractile deficit, and that prevention of denervation by IGF-1 overexpression would prevent external Ca 2+ -dependent contraction in aging mice. IGF-1 overexpression in skeletal muscle prevents age-related denervation, and prevented external Ca 2+ -dependent contraction in this work. To determine if the effects of IGF-1 overexpression are on muscle or nerve, aging mice were injected with a tetanus toxin fragment-C (TTC) fusion protein that targets IGF-1 to spinal cord motor neurons. This treatment prevented external Ca 2+ -dependent contraction. We also show evidence that injections of the IGF-1-TTC fusion protein prevent age-related alterations to the nerve terminals at the neuromuscular junctions. We conclude that the slow agerelated denervation of fast muscle fibers underlies dependence on external Ca 2+ to maintain tetanic force in a population of muscle fibers from senescent mice.

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Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging

Rodrigues

Wang

Messi

et al. 2020

J cachexia sarcopenia muscle

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Background Sarcopenia, or age‐dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co‐morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle‐wasting conditions. Interventions that can adjust neurotransmitter release to changing physiological demands depend on understanding how the SNS affects neuromuscular transmission, muscle motor innervation, and muscle mass. Methods We examined age‐dependent expression of the heart and neural crest derivative 2 (Hand2), a critical transcription factor for SN maintenance, and we tested the possibility that inducing its expression exclusively in sympathetic neurons (SN) will prevent (i) motor denervation, (ii) impaired neuromuscular junction (NMJ) transmission, and (iii) loss of muscle mass and function in old mice. To test this hypothesis, we delivered a viral vector carrying Hand2 expression or an empty vector exclusively in SNs by vein injection in 16‐month‐old C57BL/6 mice that were sacrificed 6 months later. Techniques include RNA‐sequencing, real‐time PCR, genomic DNA methylation, viral vector construct, tissue immunohistochemistry, immunoblot, confocal microscopy, electrophysiology, and in vivo mouse physical performance. Results Hand2 expression declines throughout life, but inducing its expression increased (i) the number and size of SNs, (ii) muscle sympathetic innervation, (iii) muscle weight and force and whole‐body strength, (iv) myofiber size but not muscle fibre‐type composition, (v) NMJ transmission and nerve‐evoked muscle force, and (vi) motor innervation in old mice. Additionally, the SN controls a set of genes to reduce inflammation and to promote transcription factor activity, cell signalling, and synapse in the skeletal muscle. Hand2 DNA methylation may contribute, at least partially, to gene silencing. Conclusions Selective expression of Hand2 in the mouse SNs from middle age through old age increases muscle mass and force by (i) regulating skeletal muscle sympathetic and motor innervation; (ii) improving acetylcholine receptor stability and NMJ transmission; (iii) preventing inflammation and myofibrillar protein degradation; (iv) increasing autophagy; and (v) probably enhancing protein synthesis.

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Insulin-like Growth Factor-1 Increases Skeletal Muscle Dihydropyridine Receptor α1S Transcriptional Activity by Acting on the cAMP-response Element-binding Protein Element of the Promoter Region

Cited by 26 publications

References 42 publications

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

Motor neuron targeting of IGF-1 attenuates age-related external Ca2+-dependent skeletal muscle contraction in senescent mice

Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging

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