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Sarcopenia and age-related endocrine function.

Sakuma K, Yamaguchi A - Int J Endocrinol (2012)

Bottom Line: Testosterone supplementation in large amounts and at low frequency improves muscle defects with aging but has several side effects.Although IGF-I is a potent regulator of muscle mass, its therapeutic use has not had a positive effect probably due to local IGF-I resistance.Treatment with ghrelin may ameliorate the muscle atrophy elicited by age-dependent decreases in growth hormone.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Physical Fitness, Sports and Health, Toyohashi University of Technology, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi 441-8580, Japan.

ABSTRACT
Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation. Testosterone supplementation in large amounts and at low frequency improves muscle defects with aging but has several side effects. Although IGF-I is a potent regulator of muscle mass, its therapeutic use has not had a positive effect probably due to local IGF-I resistance. Treatment with ghrelin may ameliorate the muscle atrophy elicited by age-dependent decreases in growth hormone. Ghrelin is an interesting candidate because it is orally active, avoiding the need for injections. A more comprehensive knowledge of vitamin-D-related mechanisms is needed to utilize this nutrient to prevent sarcopenia.

No MeSH data available.


Related in: MedlinePlus

(a) In young muscle, abundant serum IGF-I can stimulate protein synthesis by activating Akt/mTOR/p70S6K pathway. Akt blocks the nuclear translocation of FOXO to inhibit the expression of Atrogin-1 and MuRF and the consequent protein degradation. Abundant serum GH, which is induced by ghrelin, activates JAK2-STAT5 signaling to promote muscle-specific gene transcription necessary to hypertrophy. In young muscle, testosterone and estrogen bind these intramuscular receptors (androgen receptor and estrogen receptor (α and β)), and activate mTOR and Akt, respectively. Lower serum amount of myostatin and TNF-α failed to activate signaling candidates (Smad 2/3, NF-κB, etc.) enhancing protein degradation. (b) In sarcopenic muscle, myostatin signals through the activin receptor IIB (ActRIIB), ALK4/5 heterodimer seems to activate Smad2/3 and blocking of MyoD transactivation in an autoregulatory feedback loop. Abundant activated Smad2/3 inhibit protein synthesis probably due to blocking the functional role of Akt. The increased blood TNF-α elevates the protein degradation through IKK/NF-κB signaling and enhance an apoptosis. Lower serum amount of IGF-I, GH, and anabolic hormones (testosterone and estrogen) failed to activate signaling candidates (Akt, mTOR, STAT5, etc.) enhancing protein synthesis. The impaired regulation of FOXO by Akt results in abundant expression of Atrogin-1 and MuRF and the consequent protein degradation in sarcopenic muscle.
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fig1: (a) In young muscle, abundant serum IGF-I can stimulate protein synthesis by activating Akt/mTOR/p70S6K pathway. Akt blocks the nuclear translocation of FOXO to inhibit the expression of Atrogin-1 and MuRF and the consequent protein degradation. Abundant serum GH, which is induced by ghrelin, activates JAK2-STAT5 signaling to promote muscle-specific gene transcription necessary to hypertrophy. In young muscle, testosterone and estrogen bind these intramuscular receptors (androgen receptor and estrogen receptor (α and β)), and activate mTOR and Akt, respectively. Lower serum amount of myostatin and TNF-α failed to activate signaling candidates (Smad 2/3, NF-κB, etc.) enhancing protein degradation. (b) In sarcopenic muscle, myostatin signals through the activin receptor IIB (ActRIIB), ALK4/5 heterodimer seems to activate Smad2/3 and blocking of MyoD transactivation in an autoregulatory feedback loop. Abundant activated Smad2/3 inhibit protein synthesis probably due to blocking the functional role of Akt. The increased blood TNF-α elevates the protein degradation through IKK/NF-κB signaling and enhance an apoptosis. Lower serum amount of IGF-I, GH, and anabolic hormones (testosterone and estrogen) failed to activate signaling candidates (Akt, mTOR, STAT5, etc.) enhancing protein synthesis. The impaired regulation of FOXO by Akt results in abundant expression of Atrogin-1 and MuRF and the consequent protein degradation in sarcopenic muscle.

Mentions: Ghrelin is a 28-amino-acid peptide mainly produced by cells in the stomach, intestines, and hypothalamus [100]. Ghrelin is a natural ligand for the GH-secretagogue receptor (GHS-R), which possesses a unique fatty acid modification, an n-octanoylation, at Ser 3 [101]. Ghrelin plays a critical role in a variety of physiological processes, including the stimulation of GH secretion and regulation of energy homeostasis by stimulating food intake and promoting adiposity via a GH-independent mechanism [100]. In contrast, ghrelin inhibits the production of anorectic proinflammatory cytokines, including IL-1β, IL-6, and TNF-α [102]. Because of their combined anabolic effects on skeletal muscle and appetite, ghrelin and low-molecular-weight agonists of the ghrelin receptor are considered attractive candidates for the treatment of cachexia [103]. For example, Nagaya et al. [104] gave human ghrelin (2 μg/Kg twice daily intravenously) for 3 weeks to cachexic patients with chronic obstructive pulmonary disease in an open-label study. After ghrelin therapy, significant increases from baseline measurements were observed for body weight, lean body mass, food intake, hand grip strength, maximal inspiratory pressure, and Karnofsky performance score [104]. In another unblinded study, the same group demonstrated that treatment with human ghrelin (2 μg/Kg twice daily intravenously, 3 weeks) significantly improved several parameters (eg., lean body mass measured by dual-energy X-ray absorption and left ventricular ejection fraction) in 10 patients with chronic heart failure [105]. In a 1-year placebo-controlled study in healthy older adults over the age of 60 years given an oral ghrelin-mimetic (MK-677), an increase in appetite was observed [106]. The study did not show a significant increase in strength or function in the ghrelin-mimetic treatment group, when compared to the placebo group; however, a tendency was observed [106]. As pointed out in a recent review by Nass et al. [20], the use of this compound induces the potential deterioration of insulin sensitivity and development of diabetes mellitus in older adults with impaired glucose tolerance. Figure 1 provides an overview of several regulators for muscle mass in both young and sarcopenic mammalian muscles.


Sarcopenia and age-related endocrine function.

Sakuma K, Yamaguchi A - Int J Endocrinol (2012)

(a) In young muscle, abundant serum IGF-I can stimulate protein synthesis by activating Akt/mTOR/p70S6K pathway. Akt blocks the nuclear translocation of FOXO to inhibit the expression of Atrogin-1 and MuRF and the consequent protein degradation. Abundant serum GH, which is induced by ghrelin, activates JAK2-STAT5 signaling to promote muscle-specific gene transcription necessary to hypertrophy. In young muscle, testosterone and estrogen bind these intramuscular receptors (androgen receptor and estrogen receptor (α and β)), and activate mTOR and Akt, respectively. Lower serum amount of myostatin and TNF-α failed to activate signaling candidates (Smad 2/3, NF-κB, etc.) enhancing protein degradation. (b) In sarcopenic muscle, myostatin signals through the activin receptor IIB (ActRIIB), ALK4/5 heterodimer seems to activate Smad2/3 and blocking of MyoD transactivation in an autoregulatory feedback loop. Abundant activated Smad2/3 inhibit protein synthesis probably due to blocking the functional role of Akt. The increased blood TNF-α elevates the protein degradation through IKK/NF-κB signaling and enhance an apoptosis. Lower serum amount of IGF-I, GH, and anabolic hormones (testosterone and estrogen) failed to activate signaling candidates (Akt, mTOR, STAT5, etc.) enhancing protein synthesis. The impaired regulation of FOXO by Akt results in abundant expression of Atrogin-1 and MuRF and the consequent protein degradation in sarcopenic muscle.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368374&req=5

fig1: (a) In young muscle, abundant serum IGF-I can stimulate protein synthesis by activating Akt/mTOR/p70S6K pathway. Akt blocks the nuclear translocation of FOXO to inhibit the expression of Atrogin-1 and MuRF and the consequent protein degradation. Abundant serum GH, which is induced by ghrelin, activates JAK2-STAT5 signaling to promote muscle-specific gene transcription necessary to hypertrophy. In young muscle, testosterone and estrogen bind these intramuscular receptors (androgen receptor and estrogen receptor (α and β)), and activate mTOR and Akt, respectively. Lower serum amount of myostatin and TNF-α failed to activate signaling candidates (Smad 2/3, NF-κB, etc.) enhancing protein degradation. (b) In sarcopenic muscle, myostatin signals through the activin receptor IIB (ActRIIB), ALK4/5 heterodimer seems to activate Smad2/3 and blocking of MyoD transactivation in an autoregulatory feedback loop. Abundant activated Smad2/3 inhibit protein synthesis probably due to blocking the functional role of Akt. The increased blood TNF-α elevates the protein degradation through IKK/NF-κB signaling and enhance an apoptosis. Lower serum amount of IGF-I, GH, and anabolic hormones (testosterone and estrogen) failed to activate signaling candidates (Akt, mTOR, STAT5, etc.) enhancing protein synthesis. The impaired regulation of FOXO by Akt results in abundant expression of Atrogin-1 and MuRF and the consequent protein degradation in sarcopenic muscle.
Mentions: Ghrelin is a 28-amino-acid peptide mainly produced by cells in the stomach, intestines, and hypothalamus [100]. Ghrelin is a natural ligand for the GH-secretagogue receptor (GHS-R), which possesses a unique fatty acid modification, an n-octanoylation, at Ser 3 [101]. Ghrelin plays a critical role in a variety of physiological processes, including the stimulation of GH secretion and regulation of energy homeostasis by stimulating food intake and promoting adiposity via a GH-independent mechanism [100]. In contrast, ghrelin inhibits the production of anorectic proinflammatory cytokines, including IL-1β, IL-6, and TNF-α [102]. Because of their combined anabolic effects on skeletal muscle and appetite, ghrelin and low-molecular-weight agonists of the ghrelin receptor are considered attractive candidates for the treatment of cachexia [103]. For example, Nagaya et al. [104] gave human ghrelin (2 μg/Kg twice daily intravenously) for 3 weeks to cachexic patients with chronic obstructive pulmonary disease in an open-label study. After ghrelin therapy, significant increases from baseline measurements were observed for body weight, lean body mass, food intake, hand grip strength, maximal inspiratory pressure, and Karnofsky performance score [104]. In another unblinded study, the same group demonstrated that treatment with human ghrelin (2 μg/Kg twice daily intravenously, 3 weeks) significantly improved several parameters (eg., lean body mass measured by dual-energy X-ray absorption and left ventricular ejection fraction) in 10 patients with chronic heart failure [105]. In a 1-year placebo-controlled study in healthy older adults over the age of 60 years given an oral ghrelin-mimetic (MK-677), an increase in appetite was observed [106]. The study did not show a significant increase in strength or function in the ghrelin-mimetic treatment group, when compared to the placebo group; however, a tendency was observed [106]. As pointed out in a recent review by Nass et al. [20], the use of this compound induces the potential deterioration of insulin sensitivity and development of diabetes mellitus in older adults with impaired glucose tolerance. Figure 1 provides an overview of several regulators for muscle mass in both young and sarcopenic mammalian muscles.

Bottom Line: Testosterone supplementation in large amounts and at low frequency improves muscle defects with aging but has several side effects.Although IGF-I is a potent regulator of muscle mass, its therapeutic use has not had a positive effect probably due to local IGF-I resistance.Treatment with ghrelin may ameliorate the muscle atrophy elicited by age-dependent decreases in growth hormone.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Physical Fitness, Sports and Health, Toyohashi University of Technology, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi 441-8580, Japan.

ABSTRACT
Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation. Testosterone supplementation in large amounts and at low frequency improves muscle defects with aging but has several side effects. Although IGF-I is a potent regulator of muscle mass, its therapeutic use has not had a positive effect probably due to local IGF-I resistance. Treatment with ghrelin may ameliorate the muscle atrophy elicited by age-dependent decreases in growth hormone. Ghrelin is an interesting candidate because it is orally active, avoiding the need for injections. A more comprehensive knowledge of vitamin-D-related mechanisms is needed to utilize this nutrient to prevent sarcopenia.

No MeSH data available.


Related in: MedlinePlus