Boldine, an alkaloid from Chilean boldo tree, shields diabetic muscle from damage

A natural alkaloid extracted from the leaves of the Chilean boldo tree may hold the key to protecting skeletal muscle from one of diabetes’ most disabling complications. In a study published in Cellular and Molecular Life Sciences, a team led by Walter Vásquez and Juan C. Sáez at Pontificia Universidad Católica de Chile and Universidad de Valparaíso reports that boldine, administered at 50 mg/kg/day for four weeks, prevented the loss of muscle strength, membrane depolarization and reduced blood perfusion that develop in diabetic mice. The findings point to large-pore membrane channels as a druggable target for diabetic myopathy, a condition for which few specific treatments exist.

Skeletal muscle dysfunction is a hallmark consequence of diabetes mellitus. Patients experience reduced strength, impaired perfusion, lipid accumulation within muscle fibers and chronic inflammation, all of which erode mobility and quality of life. The Chilean researchers hypothesized that a specific class of membrane proteins — large-pore channels, including connexin-formed hemichannels and P2X7 receptors — drives much of this damage. When these channels open, they dramatically increase membrane permeability, allowing ions and signaling molecules to flood across the sarcolemma and triggering inflammatory cascades. Boldine, known for its antioxidant and anti-inflammatory properties, is a recognized inhibitor of these channels, making it an ideal candidate to test.

To model diabetes, the team injected male C57BL/6J mice with streptozotocin at 40 mg/kg/day for five days, a standard protocol that destroys insulin-producing beta cells and produces sustained hyperglycemia. Diabetic animals then received boldine for four weeks. The results were striking. Untreated diabetic mice showed markedly reduced muscle strength and depolarization of the resting membrane potential of myofibers, meaning the electrical charge across the muscle cell membrane shifted toward a less negative value, impairing excitability. Basal gastrocnemius perfusion dropped by approximately 20 percent, reflecting compromised vascular supply to the muscle. Boldine treatment prevented all three deficits, preserving strength, membrane potential and blood flow at near-normal levels.

Metabolic disruption was equally dramatic. Lipid accumulation in the muscle of diabetic mice reached 52.4 ± 3.6 percent of the measured area, compared with just 3.1 ± 1.3 percent in healthy controls. This ectopic fat deposition, a well-known feature of diabetic muscle, was reduced to 15.2 ± 4.1 percent with boldine treatment, a statistically significant rescue (p < 0.05). The alkaloid also tamed the inflammatory arm of the disease: mRNA levels of NLRP3, a core component of the inflammasome, surged 17.7-fold in diabetic muscle, and boldine cut this increase roughly in half. NLRP3 inflammasome activation is a key driver of interleukin-1β maturation and sterile inflammation, so its suppression represents a meaningful anti-inflammatory effect at the tissue level.

To dissect the cellular mechanism, the researchers turned to human myoblasts of the AB1167 line, exposed to low or high glucose with or without boldine. Under high glucose, the cells showed increased ethidium uptake — a standard readout of large-pore channel opening — along with elevated intracellular calcium, increased nitric oxide production, upregulated inflammasome-related gene expression and enhanced nuclear localization of PPARγ, a nuclear receptor that promotes lipid storage. Boldine attenuated every one of these changes, suggesting a coherent causal chain linking channel opening to metabolic and inflammatory damage.

The proposed mechanism, illustrated in the study’s graphical abstract, works as follows. In myoblasts, high glucose increases large-pore channel activity, raising cytoplasmic calcium concentration and nitric oxide generation. These signals feed back positively, further increasing the activity of connexin-formed hemichannels and P2X7 receptors, elevating levels of inflammasome components and promoting lipid accumulation. In streptozotocin-diabetic mice, de novo expression of large-pore channels in skeletal muscle contributes to reducing the resting membrane potential of myofibers, reducing muscle blood perfusion, causing weakness, activating PPARγ and driving intramuscular fat deposition. Boldine interrupts this vicious cycle at its entry point by inhibiting channel activity.

Calcium is the linchpin of this cascade. Sustained calcium influx through open large-pore channels activates calcium-dependent enzymes, including nitric oxide synthases, whose product nitric oxide then potentiates channel opening in a self-amplifying loop. The resulting inflammatory signaling upregulates NLRP3 and related genes, while PPARγ activation diverts metabolic programs toward lipid storage. By clamping the channel gate shut, boldine simultaneously protects membrane excitability, vascular reactivity and metabolic homeostasis — three domains of muscle biology that diabetes attacks in parallel.

The vascular findings deserve particular attention. A 20 percent reduction in basal muscle perfusion implies that large-pore channels are active not only in myofibers but also in the endothelial and mural cells that regulate vessel tone. Boldine’s ability to restore perfusion suggests the compound preserves vascular reactivity in the diabetic muscle microcirculation, ensuring that oxygen and nutrients continue to reach working fibers. This integrated muscle-vascular protection distinguishes the approach from strategies that target only metabolic or only inflammatory pathways.

The work, conducted across Chilean institutions including Pontificia Universidad Católica de Chile, Universidad Andrés Bello, Universidad del Bío-Bío, Universidad de Talca, Universidad Autónoma de Chile and Universidad de Valparaíso, was funded by ANID grants and published open access under a Creative Commons licence. Animal procedures were approved by the Bioethics Committee of the Universidad de Valparaíso. The authors emphasize that their effects involve inhibition of large-pore channels, reducing membrane permeability and calcium-dependent inflammatory signaling, and they highlight these channels as therapeutic targets for diabetes-induced muscle dysfunction.

Translational caveats remain. The study used a streptozotocin model of type 1-like diabetes in male mice, and human diabetic myopathy — most often associated with type 2 diabetes — involves additional metabolic complexity. Dosing, pharmacokinetics and long-term safety of boldine in humans are unestablished. Nevertheless, the convergence of in vivo and in vitro evidence, the magnitude of the lipid and inflammasome rescue, and the identification of a mechanistically coherent, druggable target make this one of the more compelling recent entries in the search for therapies against diabetic muscle disease. If future studies confirm these effects in models of type 2 diabetes and ultimately in patients, a compound derived from a traditional Chilean medicinal tree could become a genuine candidate for preserving muscle function in millions of people living with diabetes.

Subject of Research: Study showing boldine prevents diabetes-induced skeletal muscle dysfunction by inhibiting large-pore channels

Article Title: Boldine attenuates diabetes-induced skeletal muscle dysfunction

Article References: Boldine attenuates diabetes-induced skeletal muscle dysfunction. (n.d.). https://doi.org/10.1007/s00018-026-06404-w

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06404-w

Keywords: boldine, skeletal muscle, diabetes, large-pore channels, connexin hemichannels, P2X7 receptor, NLRP3 inflammasome, PPARγ, lipid accumulation, nitric oxide, calcium signaling, Peumus boldus