Diminished anabolic signaling response to insulin induced by intramuscular lipid accumulation is associated with inflammation in aging but not obesity

The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabol...

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Vydané v:	American journal of physiology. Regulatory, integrative and comparative physiology Ročník 310; číslo 7; s. R561
Hlavní autori:	Rivas, Donato A, McDonald, Devin J, Rice, Nicholas P, Haran, Prashanth H, Dolnikowski, Gregory G, Fielding, Roger A
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.04.2016
Predmet:	Aging - metabolism Animals Insulin - administration & dosage Insulin Resistance Lipid Metabolism - drug effects Lipids - biosynthesis Male Metabolism - drug effects Mice Mice, Inbred C57BL Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Myositis - metabolism Obesity - metabolism Sarcopenia - metabolism Signal Transduction - drug effects intramuscular lipids ceramide insulin inflammation aging diacylglycerol obesity sarcopenia
ISSN:	1522-1490, 1522-1490
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Abstract	The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor.
AbstractList	The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor. The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor.The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor.
Author	McDonald, Devin J Rice, Nicholas P Dolnikowski, Gregory G Haran, Prashanth H Rivas, Donato A Fielding, Roger A
Author_xml	– sequence: 1 givenname: Donato A surname: Rivas fullname: Rivas, Donato A email: donato.rivas@tufts.edu organization: Nutrition, Exercise Physiology and Sarcopenia Laboratory, Tufts University, Boston, Massachusetts; and donato.rivas@tufts.edu – sequence: 2 givenname: Devin J surname: McDonald fullname: McDonald, Devin J organization: Nutrition, Exercise Physiology and Sarcopenia Laboratory, Tufts University, Boston, Massachusetts; and – sequence: 3 givenname: Nicholas P surname: Rice fullname: Rice, Nicholas P organization: Nutrition, Exercise Physiology and Sarcopenia Laboratory, Tufts University, Boston, Massachusetts; and – sequence: 4 givenname: Prashanth H surname: Haran fullname: Haran, Prashanth H organization: Nutrition, Exercise Physiology and Sarcopenia Laboratory, Tufts University, Boston, Massachusetts; and – sequence: 5 givenname: Gregory G surname: Dolnikowski fullname: Dolnikowski, Gregory G organization: Mass Spectrometry Unit; Jean Mayer U.S. Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts – sequence: 6 givenname: Roger A surname: Fielding fullname: Fielding, Roger A organization: Nutrition, Exercise Physiology and Sarcopenia Laboratory, Tufts University, Boston, Massachusetts; and
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SubjectTerms	Aging - metabolism Animals Insulin - administration & dosage Insulin Resistance Lipid Metabolism - drug effects Lipids - biosynthesis Male Metabolism - drug effects Mice Mice, Inbred C57BL Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Myositis - metabolism Obesity - metabolism Sarcopenia - metabolism Signal Transduction - drug effects
Title	Diminished anabolic signaling response to insulin induced by intramuscular lipid accumulation is associated with inflammation in aging but not obesity
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