Role of Connexins and Pannexins in Bone and Muscle Mass and Function

Abstract Background and Aims The loss of muscle mass and function, termed sarcopenia, is an aging-related condition associated to some important diseases such as chronic kidney disease (CKD). Hyperphosphatemia has been related to both pathologies. A chronic subclinical inflammation and a dysregulated immune system function are associated to aging affecting to multiple pathways in the skeletal muscle, and this fact has been linked to the development of sarcopenia. Interleukin-15 (IL-15) is a skeletal muscle-derived cytokine which promotes muscle regeneration. The aim of this work was to analyze the role of hyperphosphatemia on the IL-15 production of the skeletal muscle and its implication in aging-related sarcopenia. Method Cultured C2C12 myoblasts were used for in vitro experiments. Cells were treated with 10 mM beta-glycerophosphate (BGP) as a phosphate donor for 2, 4, 6, 8 and 24 hours. IL-15 mRNA levels were assessed by RT-qPCR. Three groups of C57BL6 male mice were used for the in vivo studies: 5-months-old mice (young), 24-month-old mice fed with a standard diet containing 0.6 % of phosphate (old) and 24-month-old mice fed with a hypophosphatemic diet, containing a 0.2% of phosphate (old+lowPi), for the last three months before sacrifice. Muscle force was measured by a grip test. Serum phosphate levels were analyzed with a commercial kit. Quadriceps muscle samples were collected to evaluate in them the IL-15 mRNA expression by RT-qPCR. Results C2C12 cells treated with BGP show a significant decrease in the IL-15 mRNA expression. On the other hand, in vivo studies showed that old mice had an increase in serum phosphate concentration and a reduction in forelimb strength and muscle mass, compared to young mice. Old animals fed with the hypophosphatemic diet displayed lower levels of phosphate serum linked to an improvement in the muscle mass and function. IL-15 expression of quadriceps muscle was reduced in old mice compared to young mice, whereas those values were increased in old mice fed with the low phosphate diet. Furthermore, there was a negative correlation between IL-15 expression levels and serum phosphate concentrations and a positive correlation between IL-15 and forelimb strength and muscle mass, suggesting that a decreased IL-15 expression affects muscle function. Conclusion High extracellular phosphate concentrations decrease IL-15 mRNA expression in myoblasts, and it is correlated with low IL-15 mRNA expression in the quadriceps muscle isolated from old mice. This reduction was associated to a decreased muscular strength and muscle mass, whereas the dietary restriction of phosphate improved these features. These results point to a role of hyperphosphatemia in the impaired immune system function, disrupting the skeletal muscle function, and this could be involved in aging and CKD-related sarcopenia.

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Activation of the CRF 2 receptor modulates skeletal muscle mass under physiological and pathological conditions

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00081.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E889-E898 ◽

Cited By ~ 17

Author(s):

Richard T. Hinkle ◽

Elizabeth Donnelly ◽

David B. Cody ◽

Steven Samuelsson ◽

Jana S. Lange ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Nerve Damage ◽

Skeletal Muscle Atrophy ◽

Function Loss ◽

Selective Agonists ◽

And Function ◽

First Time

Two receptors activated by the corticotropin-releasing factor (CRF) family of peptides have been identified, the CRF 1 receptor (CRF1R) and the CRF 2 receptor (CRF2R). Of these, the CRF2R is expressed in skeletal muscle. To understand the role of the CRF2R in skeletal muscle, we utilized CRFR knockout mice and CRF2R-selective agonists to modulate nerve damage and corticosteroid- and disuse-induced skeletal muscle atrophy in mice. These analyses demonstrated that activation of the CRF2R decreased nerve damage and corticosteroid- and disuse-induced skeletal muscle mass and function loss. In addition, selective activation of the CRF2R increased nonatrophy skeletal muscle mass. Thus we describe for the first time a novel activity of the CRF2R, modulation of skeletal muscle mass.

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Recent advances and future avenues in understanding the role of adipose tissue cross talk in mediating skeletal muscle mass and function with ageing

GeroScience ◽

10.1007/s11357-021-00322-4 ◽

2021 ◽

Author(s):

Andrew Wilhelmsen ◽

Kostas Tsintzas ◽

Simon W. Jones

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Muscle Mass ◽

Extracellular Vesicles ◽

Cross Talk ◽

Skeletal Muscle Mass ◽

Activity Level ◽

Age Related ◽

And Function

AbstractSarcopenia, broadly defined as the age-related decline in skeletal muscle mass, quality, and function, is associated with chronic low-grade inflammation and an increased likelihood of adverse health outcomes. The regulation of skeletal muscle mass with ageing is complex and necessitates a delicate balance between muscle protein synthesis and degradation. The secretion and transfer of cytokines, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), both discretely and within extracellular vesicles, have emerged as important communication channels between tissues. Some of these factors have been implicated in regulating skeletal muscle mass, function, and pathologies and may be perturbed by excessive adiposity. Indeed, adipose tissue participates in a broad spectrum of inter-organ communication and obesity promotes the accumulation of macrophages, cellular senescence, and the production and secretion of pro-inflammatory factors. Pertinently, age-related sarcopenia has been reported to be more prevalent in obesity; however, such effects are confounded by comorbidities and physical activity level. In this review, we provide evidence that adiposity may exacerbate age-related sarcopenia and outline some emerging concepts of adipose-skeletal muscle communication including the secretion and processing of novel myokines and adipokines and the role of extracellular vesicles in mediating inter-tissue cross talk via lncRNAs and miRNAs in the context of sarcopenia, ageing, and obesity. Further research using advances in proteomics, transcriptomics, and techniques to investigate extracellular vesicles, with an emphasis on translational, longitudinal human studies, is required to better understand the physiological significance of these factors, the impact of obesity upon them, and their potential as therapeutic targets in combating muscle wasting.

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The role of diet quality and dietary patterns in predicting muscle mass and function in men over a 15-year period

Osteoporosis International ◽

10.1007/s00198-021-06012-3 ◽

2021 ◽

Author(s):

J. A. Davis ◽

M. Mohebbi ◽

F. Collier ◽

A. Loughman ◽

H. Staudacher ◽

...

Keyword(s):

Muscle Mass ◽

Diet Quality ◽

Dietary Patterns ◽

And Function

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Role of Myokines in Regulating Skeletal Muscle Mass and Function

Frontiers in Physiology ◽

10.3389/fphys.2019.00042 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 50

Author(s):

Jong Han Lee ◽

Hee-Sook Jun

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

And Function

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The role of attenuated redox and heat shock protein responses in the age-related decline in skeletal muscle mass and function

Essays in Biochemistry ◽

10.1042/ebc20160088 ◽

2017 ◽

Vol 61 (3) ◽

pp. 339-348 ◽

Cited By ~ 11

Author(s):

Anne McArdle ◽

Malcolm J. Jackson

Keyword(s):

Skeletal Muscle ◽

Heat Shock ◽

Muscle Mass ◽

Stress Responses ◽

Redox Regulation ◽

Experimental Models ◽

Age Related ◽

Shock Proteins ◽

And Function

The loss of muscle mass and weakness that accompanies ageing is a major contributor to physical frailty and loss of independence in older people. A failure of muscle to adapt to physiological stresses such as exercise is seen with ageing and disruption of redox regulated processes and stress responses are recognized to play important roles in theses deficits. The role of redox regulation in control of specific stress responses, including the generation of heat shock proteins (HSPs) by muscle appears to be particularly important and affected by ageing. Transgenic and knockout studies in experimental models in which redox and HSP responses were modified have demonstrated the importance of these processes in maintenance of muscle mass and function during ageing. New data also indicate the potential of these processes to interact with and influence ageing in other tissues. In particular the roles of redox signalling and HSPs in regulation of inflammatory pathways appears important in their impact on organismal ageing. This review will briefly indicate the importance of this area and demonstrate how an understanding of the manner in which redox and stress responses interact and how they may be controlled offers considerable promise as an approach to ameliorate the major functional consequences of ageing of skeletal muscle (and potentially other tissues) in man.

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Development of age-related loss of muscle mass and function – role of oxidative DNA damage repair systems

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.12.335 ◽

2021 ◽

Vol 165 ◽

pp. 30-31

Author(s):

Kat Kumiscia ◽

Shahjahan Shigdar ◽

Carole Proctor ◽

Daryl Shanley ◽

Euan Owen ◽

...

Keyword(s):

Dna Damage ◽

Muscle Mass ◽

Oxidative Dna Damage ◽

Dna Damage Repair ◽

Age Related ◽

Damage Repair ◽

Repair Systems ◽

And Function

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Exploring the Impact of Obesity on Skeletal Muscle Function in Older Age

Frontiers in Nutrition ◽

10.3389/fnut.2020.569904 ◽

2020 ◽

Vol 7 ◽

Author(s):

Paul T. Morgan ◽

Benoit Smeuninx ◽

Leigh Breen

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Weight Bearing ◽

Research Field ◽

Older Age ◽

Older Individuals ◽

And Function ◽

The Impact

Sarcopenia is of important clinical relevance for loss of independence in older adults. The prevalence of obesity in combination with sarcopenia (“sarcopenic-obesity”) is increasing at a rapid rate. However, whilst the development of sarcopenia is understood to be multi-factorial and harmful to health, the role of obesity from a protective and damaging perspective on skeletal muscle in aging, is poorly understood. Specifically, the presence of obesity in older age may be accompanied by a greater volume of skeletal muscle mass in weight-bearing muscles compared with lean older individuals, despite impaired physical function and resistance to anabolic stimuli. Collectively, these findings support a potential paradox in which obesity may protect skeletal muscle mass in older age. One explanation for these paradoxical findings may be that the anabolic response to weight-bearing activity could be greater in obese vs. lean older individuals due to a larger mechanical stimulus, compensating for the heightened muscle anabolic resistance. However, it is likely that there is a complex interplay between muscle, adipose, and external influences in the aging process that are ultimately harmful to health in the long-term. This narrative briefly explores some of the potential mechanisms regulating changes in skeletal muscle mass and function in aging combined with obesity and the interplay with sarcopenia, with a particular focus on muscle morphology and the regulation of muscle proteostasis. In addition, whilst highly complex, we attempt to provide an updated summary for the role of obesity from a protective and damaging perspective on muscle mass and function in older age. We conclude with a brief discussion on treatment of sarcopenia and obesity and a summary of future directions for this research field.

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