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Treadmill running induces satellite cell activation in diabetic mice.

ABSTRACT: Skeletal muscle-derived stem cells, termed as satellite cells, play essential roles in regeneration after muscle injury in adult skeletal muscle. Diabetes mellitus (DM), one of the most common metabolic diseases, causes impairments of satellite cell function. However, the studies of the countermeasures for the DM-induced dysfunction of satellite cells have been poor. Here, we investigated the effects of chronic running exercise on satellite cell activation in diabetic mice focused on the molecular mechanism including Notch and Wnt signaling, which are contribute to the fate determination of satellite cells. Male C57BL/6 mice 4 weeks of age were injected with streptozotocin and were randomly divided into runner group and control group. Runner group mice were performed treadmill running for 4 weeks. DM attenuated satellite cell activation and the expressions of the components of Notch and Wnt signaling. However, chronic running resulted in activation of satellite cells in diabetic mice and salvaged the inactivity of Wnt signaling but not Notch signaling. Our results suggest that chronic running induces satellite cell activation via upregulation of Wnt signaling in diabetic as well as normal mice.

SUBMITTER: Fujimaki S

PROVIDER: S-EPMC5613654 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Treadmill running induces satellite cell activation in diabetic mice.

Fujimaki Shin S Wakabayashi Tamami T Asashima Makoto M Takemasa Tohru T Kuwabara Tomoko T

Biochemistry and biophysics reports 20160728

Skeletal muscle-derived stem cells, termed as satellite cells, play essential roles in regeneration after muscle injury in adult skeletal muscle. Diabetes mellitus (DM), one of the most common metabolic diseases, causes impairments of satellite cell function. However, the studies of the countermeasures for the DM-induced dysfunction of satellite cells have been poor. Here, we investigated the effects of chronic running exercise on satellite cell activation in diabetic mice focused on the molecul ...[more]

PMID: 28955935

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Project description:Background:Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. Methods:We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7CreER/+; ROSA26mTmG/+ mice. SCs were depleted in Pax7CreER/+; ROSA26DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. Results:Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. Conclusion:The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.

Project description:Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular disease (CVD) outcomes, supporting VCAM1's role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1's release or its interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane-bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs). Still, the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from an inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β activation in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease, particularly in diabetes, holds significant therapeutic potential.

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Treadmill running induces satellite cell activation in diabetic mice.

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Treadmill running induces satellite cell activation in diabetic mice.

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