The cryptochromes are flavoproteins that either individually or synergistically respond to light and magnetic field directionality as well as are implicated in circadian rhythm entrainment and development. Single brief exposures (10 min) to low energy (1.5 mT) pulsed electromagnetic fields (PEMFs) were previously shown to enhance myogenesis by stimulating transient receptor potential canonical 1 (TRPC1)-mediated Ca²⁺ entry, whereby downwardly directed fields produced greater myogenic enhancement than upwardly directed fields. Here, we show that growth in the dark results in myoblasts losing their sensitivity to both magnetic field exposure and directionality. By contrast, overexpressing or silencing cryptochrome circadian regulator 2 (CRY2) in myoblasts enhances or reduces PEMF responses, respectively, under conditions of ambient light. Reducing cellular flavin adenine dinucleotide (FAD) content by silencing riboflavin kinase (RFK) attenuated responsiveness to PEMFs and inhibited selectivity for magnetic field direction. The upregulation of TRPC1 and cell cycle regulatory proteins typically observed in response to PEMF exposure was instead attenuated by upwardly directed magnetic fields, growth in the darkness, magnetic shielding, or the silencing of CRY2 or RFK. A physical interaction between CRY2 and TRPC1 was detected using coimmunoprecipitation and immunofluorescence, revealing their co-translocation into the nucleus after PEMF exposure. These results implicate CRY2 in an identified TRPC1-dependent magnetotransduction myogenic cascade.

Background/Objectives: Doxorubicin (DOX) is commonly used as a chemotherapeutic agent for the treatment of breast cancer. Nonetheless, its systemic delivery via intravenous injection and toxicity towards healthy tissues commonly result in a broad range of detrimental side effects. Breast cancer severity was previously shown to be correlated with TRPC1 channel expression that conferred upon it enhanced vulnerability to pulsed electromagnetic field (PEMF) therapy. PEMF therapy was also previously shown to enhance breast cancer cell vulnerability to DOX in vitro and in vivo that correlated with TRPC1 expression and mitochondrial respiratory rates. Methods: DOX uptake was assessed by measuring its innate autofluorescence within murine 4T1 or human MCF7 breast cancer cells following magnetic exposure. Cellular vulnerability to doxorubicin uptake was assessed by monitoring mitochondrial activity and cellular DNA content. Results: Here, we demonstrate that 10 min of PEMF exposure could augment DOX uptake into 4T1 and MCF7 breast cancer cells. DOX uptake could be increased by TRPC1 overexpression, whereas inhibiting the activity of TRPC1 channels with SKF-96356 or genetic knockdown, precluded DOX uptake. PEMF exposure enhances DOX-mediated killing of breast cancer cells, reducing the IC₅₀ value of DOX by half, whereas muscle cells, representative of collateral tissues, were less sensitive to PEMF-enhanced DOX-mediated cytotoxicity. Vesicular loading of DOX correlated with TRPC1 expression. Conclusions: This study presents a novel TRPC1-mediated mechanism through which PEMF therapy may enhance DOX cytotoxicity in breast cancer cells, paving the way for the development of localized non-invasive PEMF platforms to improve cancer outcomes with lower systemic levels of DOX.

This study compared the metabolic consequences of fecal microbiota transplantation (FMT) from donor mice that had been either administered pulsed electromagnetic field (PEMF) therapy or exercised to recipient mice fed a high-fat diet (HFD). Eight weeks of PEMF treatment (10 min/week) enhanced PGC-1α-associated mitochondrial and metabolic gene expression in white and brown adipose to a greater degree than eight weeks of exercise (30–40 min/week). FMT from PEMF-treated donor mice recapitulated these adipogenic adaptations in HFD-fed recipient mice more faithfully than FMT from exercised donors. Direct PEMF treatment altered hepatic phospholipid composition, reducing long-chain ceramides (C16:0) and increasing very long-chain ceramides (C24:0), which could be transferred to PEMF-FMT recipient mice. FMT from PEMF-treated mice was also more effective at recovering glucose tolerance than FMT from exercised mice. PEMF treatment also enhanced bone density in both donor and HFD recipient mice. The gut Firmicutes/Bacteroidetes (F/B) ratio was lowest in both the directly PEMF-exposed and PEMF-FMT recipient mouse groups, consistent with a leaner phenotype. PEMF treatment, either directly applied or via FMT, enhanced adipose thermogenesis, ceramide levels, bone density, hepatic lipids, F/B ratio, and inflammatory blood biomarkers more than exercise. PEMF therapy may represent a non-invasive and non-strenuous method to ameliorate metabolic disorders.

Maternal metabolic dysfunction adversely influences embryonic muscle oxidative capacity and mitochondrial biogenesis, increasing the child’s long-term risks of developing obesity and metabolic syndrome in later life. This pilot study explored the mechanistic basis of embryonic muscle metabolic programming, employing non-invasive magnetic field exposures. Brief (10 min) exposure to low-energy (1.5 milliTesla at 50 Hertz) pulsing electromagnetic fields (PEMFs) has been shown in mammals to promote oxidative muscle development, associated with enhanced muscular mitochondriogenesis, augmented lipid metabolism, and attenuated inflammatory status. In this study, quail eggs were used as a model system to investigate the potential of analogous PEMF therapy to modulate embryonic muscle oxidative capacity independently of maternal influence. Quail eggs were administered five 10-min PEMF exposures to either upward-directed or downward-directed magnetic fields over 13 days. Embryos receiving magnetic treatment exhibited increased embryo weight, size, and survival compared to non-exposed controls. Upward exposure was associated with larger embryos, redder breast musculature, and upregulated levels of PPAR-α and PGC-1α, transcriptional regulators promoting oxidative muscle development, mitochondriogenesis, and angiogenesis, whereas downward exposure augmented collagen levels and reduced angiogenesis. Exposure to upward PEMFs may hence serve as a method to promote embryonic growth and oxidative muscle development and improve embryonic mortality.

Preclinical studies have shown that the blood from female mice exposed weekly to magnetic fields inhibited breast cancer growth. This double-blind randomized controlled trial investigated whether analogous magnetic therapy could produce similar anticancer sera from human subjects. Twenty-six healthy adult females (ages 30–45) were assigned to either a magnetic therapy group, receiving twice weekly 1 mT magnetic exposures (10 min/session) for 4 weeks, or a control group, who underwent identical sham exposure. Blood sera were evaluated for their capacity to modulate breast cancer-related cellular responses and epithelial–mesenchymal transition. The sera from the magnetic therapy group subjects exhibited significant anticancer effects that were strongest one month after the last magnetic exposure, whereas the sera from unexposed females or unexposed or exposed males showed no effect. Female sera from the magnetic therapy group (n = 12) reduced breast cancer cell proliferation (16.1%), migration (11.8%) and invasion (28.2%) and reduced the levels of key EMT markers relative to the control sera (n = 14). Magnetic therapy modulated the serum levels of angiogenic and myogenic biomarkers in a manner consistent with improved cancer management. Muscle-targeted magnetic therapy holds the potential to enhance the anticancer properties of human blood via an adaptive process, akin to exercise training.