The influence of skeletal muscle on systemic aging and lifespan

Demontis, Fabio; Piccirillo, Rosanna; Goldberg, Alfred L.; Perrimon, Norbert

doi:10.1111/acel.12126

Cited by 200 publications

(159 citation statements)

References 109 publications

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“…In recent years, significant advances have been made in understanding the pathophysiological functions of skeletal muscle and the involvement of functional abnormalities of skeletal muscle in various disorders (1). Impairment of insulin resistance, together with b-cell secretary function defects, is a key contributor to the occurrence of Type 2 diabetes mellitus (DM).…”

Section: Skeletal Muscle and Adipokinesmentioning

confidence: 99%

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Skeletal Muscle Is an Endocrine Organ

2014

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Abstract. Skeletal muscle plays a key role in postural retention as well as locomotion for maintaining the physical activities of human life. Skeletal muscle has a second role as an elaborate energy production and consumption system that influences the whole body's energy metabolism. Skeletal muscle is a specific organ that engenders a physical force, and exercise training has been known to bring about multiple benefits for human health maintenance and/or improvement. The mechanisms underlying the improvement of the human physical condition have been revealed: skeletal muscle synthesizes and secretes multiple factors, and these muscle-derived factors, so-called as myokines, exert beneficial effects on peripheral and remote organs. In this short review, we focus on the third aspect of skeletal muscle function -namely, the release of multiple types of myokines, which constitute a broad network for regulating the function of remote organs as well as skeletal muscle itself. We conclusively show that skeletal muscle is one of the endocrine organs and that understanding the mechanisms of production and secretion of myokines may lead to a new pharmacological approach for treatment of clinical disorders.

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Section: Skeletal Muscle and Adipokinesmentioning

confidence: 99%

“…A recent in vitro study has pointed out the close interaction between skeletal muscle myokines and bone marrow-derived cell function (44). Maintenance of skeletal muscle health status has been shown to have an influence on systemic age-related disorders (45).…”

Section: Myokines As Therapeutic and Pharmacologic Targetsmentioning

confidence: 99%

Skeletal Muscle Is an Endocrine Organ

2014

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“…Besides its recognized role in mobility, posture, heat regulation, and endocrine function, the skeletal muscle plays a central role in whole body metabolism, which affects systemic aging and lifespan (Demontis et al ., 2013). Cohort studies show that strength is lost two‐ to five‐times faster than muscle mass with age (Goodpaster et al ., 2006), and its loss is a more consistent risk factor for disability and death (Newman et al ., 2006).…”

Section: Introductionmentioning

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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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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“…The central nervous system (CNS) in particular integrates information regarding the status of peripheral metabolic processes via hormonal signaling and directs energy homeostasis and feeding behavior (1). In addition, metabolic changes in a peripheral organ can affect the physiology of other peripheral organs (2,3). The skeletal muscle system, which is newly recognized as playing endocrine-related roles, produces myokines after exercise to target other metabolic organs (liver, adipose tissue, pancreas, gut, and bone) and modulates systemic energy homeostasis (4).…”

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confidence: 99%

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

Song

Owusu-Ansah

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial dysfunction has been associated with obesity and metabolic disorders. However, whether mitochondrial perturbation in a single tissue influences mitochondrial function and metabolic status of another distal tissue remains largely unknown. We analyzed the nonautonomous role of muscular mitochondrial dysfunction in Drosophila. Surprisingly, impaired muscle mitochondrial function via complex I perturbation results in simultaneous mitochondrial dysfunction in the fat body (the fly adipose tissue) and subsequent triglyceride accumulation, the major characteristic of obesity. RNA-sequencing (RNA-seq) analysis, in the context of muscle mitochondrial dysfunction, revealed that target genes of the TGF-β signaling pathway were induced in the fat body. Strikingly, expression of the TGF-β family ligand, Activin-β (Actβ), was dramatically increased in the muscles by NF-κB/Relish (Rel) signaling in response to mitochondrial perturbation, and decreasing Actβ expression in mitochondrial-perturbed muscles rescued both the fat body mitochondrial dysfunction and obesity phenotypes. Thus, perturbation of muscle mitochondrial activity regulates mitochondrial function in the fat body nonautonomously via modulation of Activin signaling.mitochondrial synchrony | Activin-β | complex I perturbation | NF-κB/Relish | lipid metabolism I ndividual organs in a multicellular organism, besides performing their respective roles, must communicate with other organs to maintain systemic homeostasis. The central nervous system (CNS) in particular integrates information regarding the status of peripheral metabolic processes via hormonal signaling and directs energy homeostasis and feeding behavior (1). In addition, metabolic changes in a peripheral organ can affect the physiology of other peripheral organs (2, 3). The skeletal muscle system, which is newly recognized as playing endocrine-related roles, produces myokines after exercise to target other metabolic organs (liver, adipose tissue, pancreas, gut, and bone) and modulates systemic energy homeostasis (4).Mitochondria are semiautonomous organelles that integrate multiple physiological signals. Growing evidence indicates that mitochondrial alterations in one organ leads to abnormalities in biological processes in distal organs through hormonal signaling (5, 6). In addition to exercise, which induces mitochondrial activity and improves muscle performance, mitochondrial perturbationassociated muscle injury is also sufficient to modulate functions of other organs and change systemic outcomes via myokine production. For example, in mammals, mitochondrial dysfunction due to disruption of autophagic function in skeletal muscles results in elevated production of muscular FGF21 that triggers browning of white adipose tissue and increases lipid mobilization (7). Further, in Drosophila, mild mitochondrial distress in adult muscles delays aging via an increase of muscular ImpL2 production and remote suppression of insulin signaling in the fat body and brain (8). Despite these examples, molecula...

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The influence of skeletal muscle on systemic aging and lifespan

Cited by 200 publications

References 109 publications

Skeletal Muscle Is an Endocrine Organ

Skeletal Muscle Is an Endocrine Organ

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

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

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