Vitamin D Shields Wasted Muscle After Spinal Cord Injury by Rebuilding Mitochondria

Vitamin D, the sunshine hormone best known for building bones, may also hold the key to one of the most devastating consequences of spinal cord injury: the rapid melting away of the muscles below the site of damage. A new study published in the Journal of Cachexia, Sarcopenia and Muscle reports that daily vitamin D supplementation dramatically slowed muscle wasting in mice with completely severed spinal cords, and that the effect appears to be driven by a previously unrecognised molecular pathway linking the vitamin to cellular energy production. The findings, which also draw on clinical measurements from patients with chronic spinal cord injury, point to a cheap and widely available nutrient as a potential therapy for a condition that currently has few effective treatments.

The clinical starting point was strikingly simple. Researchers at Zhongda Hospital of Southeast University recruited twelve patients with traumatic spinal cord injuries at the cervical or thoracic level, all of whom had been injured more than six months earlier and had undergone surgical treatment. Using dual-energy X-ray absorptiometry, the team measured each patient’s appendicular skeletal muscle mass and adjusted it for height to produce a muscle index. They also measured circulating levels of 25-hydroxyvitamin D3, the standard blood marker of vitamin D status. Ten of the twelve patients had deficient or insufficient levels, and across the group the correlation was unmistakable: the lower the vitamin D level, the lower the muscle index, with the association explaining roughly sixty-five percent of the variation between patients.

Correlation alone cannot prove that vitamin D deficiency causes muscle loss, so the team turned to an animal model designed to answer the causal question. Eight-week-old male C57BL/6 mice underwent complete transection of the spinal cord at the tenth thoracic vertebra, a severe injury that produces total hindlimb paralysis. Beginning three days after surgery, one group of injured mice received a daily oral dose of calcitriol, the active form of vitamin D, dissolved in coconut oil, while injured controls received the oil vehicle alone. Sham-operated animals received each treatment as well. The dosing was deliberately modest, and the researchers monitored serum calcium, phosphate, creatinine and urea nitrogen throughout the experiment to confirm that the supplement caused no hypercalcaemia or kidney stress.

The results were visible to the naked eye. Over four weeks, injured mice given the vehicle lost weight steadily, while vitamin D-treated injured animals maintained significantly higher body weights, a difference that reached the highest level of statistical significance by the end of the study. Hindlimb circumference, a simple proxy for leg muscle bulk, was also better preserved in the treated group. When the researchers dissected the tibialis anterior, extensor digitorum longus, gastrocnemius and soleus muscles at the twenty-eight-day endpoint, the vitamin D-supplemented animals had significantly heavier gastrocnemius muscles relative to body size, and histological staining showed that their muscle fibres retained a larger, more regular cross-sectional shape than the shrunken, irregular fibres of untreated injured mice.

Perhaps the most intriguing finding concerned not how much muscle remained, but what kind. Skeletal muscle comes in distinct fibre types: slow-twitch oxidative Type I and IIA fibres, which are packed with mitochondria and built for endurance and postural support, and fast-twitch glycolytic Type IIB fibres, which generate power quickly but fatigue rapidly. After spinal cord injury, muscle reliably shifts away from the oxidative phenotype toward the fatigable glycolytic one, a remodelling that compounds the functional losses caused by denervation. In this study, the soleus, a predominantly slow muscle, underwent an especially dramatic conversion toward Type IIB fibres after injury. Vitamin D treatment almost completely prevented that conversion, preserving the proportions of oxidative fibres in the soleus and gastrocnemius and blunting the shift in the tibialis anterior.

To understand how a vitamin could accomplish such a feat, the researchers performed quantitative proteomics on the gastrocnemius muscles, using high-resolution mass spectrometry to compare protein expression across all four experimental groups. The analysis identified 171 proteins that were disrupted by spinal cord injury and then pushed back toward normal levels by vitamin D treatment. When these proteins were mapped onto biological pathways, one theme dominated: cellular energy metabolism, with glycolysis and gluconeogenesis among the most significantly enriched processes. In other words, the injured muscle was in a state of profound metabolic derangement, and vitamin D appeared to be steering it back toward equilibrium.

Within that set of rescued proteins, two stood out. The first, TIGAR, is a multifunctional regulator that suppresses excessive glycolysis and diverts glucose into the pentose phosphate pathway, boosting production of NADPH, a molecule cells use to defuse oxidative stress. TIGAR is highly expressed in skeletal muscle and has been shown in earlier work to be essential for maintaining mitochondrial function and exercise endurance, partly through activation of the SIRT1–PGC-1α signalling axis. The second, FBP2, is the muscle-specific form of fructose-1,6-bisphosphatase, an enzyme with non-canonical roles that include shielding mitochondria from stress-induced damage. In the injured, untreated mice, TIGAR expression had fallen to forty-four percent of sham levels and FBP2 to thirty-nine percent. Vitamin D supplementation raised TIGAR by 1.68-fold and FBP2 by 1.79-fold compared with untreated injured animals, and Western blotting confirmed both changes.

Because TIGAR is a known guardian of mitochondrial health, the team next examined the ultrastructure of the muscle directly with transmission electron microscopy. In healthy mice, mitochondria sat in orderly ranks on either side of the Z-line, the boundary that segments the contractile machinery of each muscle fibre. After spinal cord injury, that architecture collapsed: the Z-lines broke down, the mitochondrial arrangement became disordered, and the number of mitochondria per unit area plummeted. In the vitamin D-treated injured mice, mitochondrial morphology and arrangement were markedly improved, and mitochondrial density was significantly restored. The picture that emerges is coherent: vitamin D upregulates TIGAR and FBP2, which restores the muscle’s metabolic machinery and, with it, the mitochondrial population that oxidative fibres depend on, thereby preserving both the size and the metabolic identity of the denervated tissue.

The findings fit into a growing body of evidence that vitamin D acts directly on muscle rather than merely on bone. The vitamin D receptor is present in skeletal muscle cells, localised to both cytoplasm and nucleus, and human studies using phosphorus-31 magnetic resonance spectroscopy have shown that supplementation improves the rate of mitochondrial oxidative phosphorylation in muscle. Vitamin D deficiency has been linked to reduced mitochondrial activity and heightened oxidative stress in multiple tissues, and supplementation can reverse these defects. The new study extends this framework to the extreme case of denervation, proposing a vitamin D–TIGAR–mitochondrial axis as the mechanism by which the nutrient protects muscle that has lost its nerve supply.

Important caveats remain before the clinic should change its practice. The mouse experiments used a modest dose of the active hormone over twenty-five days in a complete transection model, which does not capture every clinical scenario; the motor improvements seen in treated mice, while statistically significant, were partial. The authors themselves note that the next step is to establish causality for the TIGAR pathway, ideally using muscle-specific TIGAR knockout mice, and to complement the morphological data with direct measurements of muscle contractility and fatigue resistance. Still, given that vitamin D deficiency is highly prevalent in people with spinal cord injury and is already an independent risk factor for poor motor recovery, the prospect that a simple, safe supplement could slow the wasting of paralysed muscle, preserve its oxidative character, and improve downstream metabolic health is a compelling one. For a condition in which therapeutic options for muscle loss remain scarce, the humble sunshine vitamin may deserve a central place in the treatment plan.

Subject of Research: Vitamin D supplementation and skeletal muscle atrophy after spinal cord injury

Article Title: Vitamin D Ameliorates Skeletal Muscle Atrophy After Spinal Cord Injury by Upregulating TIGAR and Enhancing Mitochondrial Function

Article References: Dong, Z., Li, N., Guo, Y., Sun, H., Shi, W., Zhou, M., Tong, X., Wang, Z., Qian, F., & Guo, Y. (2026). Vitamin D Ameliorates Skeletal Muscle Atrophy After Spinal Cord Injury by Upregulating TIGAR and Enhancing Mitochondrial Function. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70401. https://doi.org/10.1002/jcsm.70401

Image Credits: AI Generated

DOI: 10.1002/jcsm.70401

Keywords: vitamin D, spinal cord injury, muscle atrophy, TIGAR, mitochondria, sarcopenia, muscle fibre types, proteomics, metabolism, rehabilitation, Vitamin, Ameliorates