Vitamin C plays a crucial role in the repair of connective tissue, especially in cases of injury or strain involving collagen structures — typical in sports that place high demands on connective tissue and carry an increased risk of its damage. Collagen is the most abundant structural protein in the human body. Therefore, ascorbic acid is considered an essential compound for collagen synthesis, potentially shortening the recovery period required for the healing of ligaments and other connective structures.
Introduction
The topic of vitamin C supplementation in musculoskeletal medicine — particularly in the treatment of locomotor disorders such as sports and other injuries where the integrity of collagen structures is compromised — is the subject of numerous studies. One such study was published in the journal Amino Acids, exploring the specific role of vitamin C in collagen synthesis.¹ It investigated the influence of vitamin C on amino acid sequence, interaction, and alignment during collagen formation. The research utilized density functional theory (DFT) to study the mechanism of action of vitamin C in terms of the thermodynamics and structure of collagen synthesis reactions.
Collagen Synthesis
Collagen is a protein characterized by its triple-helix structure. It is composed primarily of the amino acids glycine, proline, hydroxyproline, and hydroxylysine. Collagen synthesis takes place on polyribosomes attached to the rough endoplasmic reticulum (rER). The resulting polypeptide chains, known as protocollagen, are transported into the cisternae of the rER, where initial glycosylation and hydroxylation occur. Hydroxylation modifies proline and lysine residues into hydroxyproline and hydroxylysine. Registration peptides at the end of each protocollagen chain prevent premature intracellular polymerization and assist in forming the triple helix — three protocollagen chains combine to create procollagen.
Procollagen is then transported to the Golgi apparatus, condensed, and enclosed within secretory vesicles, which release it into the extracellular space via exocytosis. The enzyme procollagen peptidase cleaves the registration peptides, producing tropocollagen. Neighboring cells align tropocollagen in a staggered fashion, forming collagen fibrils and, subsequently, collagen fibers. These fibers are stabilized by lysyl oxidase, which creates covalent bonds between lysine and hydroxylysine residues of adjacent tropocollagen molecules.
The Role of Vitamin C as a Cofactor
In the synthesis of all collagen types, the formation of procollagen through the incorporation of proline and glycine requires vitamin C. Collagen molecules consist of three polypeptide alpha chains in a triple-helix arrangement. Ascorbic acid is an indispensable cofactor for hydroxylase enzymes necessary for collagen synthesis. It is essential for the hydroxylation of proline and lysine into hydroxyproline and hydroxylysine.
In the reaction converting proline to 5-hydroxyproline (catalyzed by the hypoxia-inducible enzyme prolyl hydroxylase, HIF-PHDs), the enzyme’s iron atom transitions from Fe²⁺ to Fe³⁺ and then Fe⁴⁺ before hydroxyproline is released. Vitamin C reduces HIF-PHD, reactivating the catalytic cycle and stabilizing the alpha chains. Additionally, vitamin C is vital for glycosylation and stabilization of the triple-helix procollagen structure.
The referenced study used simulation modeling and DFT methods to explore vitamin C’s role in amino acid sequencing during collagen synthesis. Results showed that vitamin C significantly enhances the efficiency of forming the Gly-Hyp-Pro (glycine-hydroxyproline-proline) sequence, crucial in collagen structure. Without vitamin C, the conversion of proline to hydroxyproline halts, impeding collagen synthesis. Vitamin C not only drives this reaction but also assists in hydroxyproline release from the enzyme. The data suggest that vitamin C prevents unwanted interactions and promotes targeted amino acid responses essential for repairing connective tissue. This underscores the importance of sufficient vitamin C supplementation in the healing of damaged connective tissue.²
The Antioxidant Role of Vitamin C
Beyond its role in collagen synthesis, vitamin C functions as a powerful antioxidant, neutralizing reactive oxygen species (ROS) that contribute to cell apoptosis during inflammation. Studies also suggest vitamin C may stimulate tendon and bone stem cell mobilization, promote fibroblast differentiation, and accelerate healing. According to preclinical studies reviewed in a published systematic review, vitamin C may speed up fracture healing, increase type I collagen production, and reduce oxidative stress in connective tissues.
Vitamin C is a safe compound, and oral supplementation appears to be a promising and secure adjunct to musculoskeletal injury treatment. Intake should be adjusted according to individual needs.
References
- Chugaeva EY, Raouf M, et al. Effects of L-ascorbic acid (C6H8O6: Vit-C) on collagen amino acids: DFT study. Amino Acids. 2023. doi: 10.1007/s00726-023-03339-5. Online ahead of print.
- DePhillipo NN, Aman ZS, Kennedy MI, et al. Efficacy of vitamin C supplementation on collagen synthesis and oxidative stress after musculoskeletal injuries: A systematic review. Orthop J Sports Med. 2018;6(10):2325967118804544.