Nutritional Interventions to Attenuate Quadriceps Muscle Deficits following Anterior Cruciate Ligament Injury and Reconstruction

Abstract

Following anterior cruciate ligament (ACL) injury, quadriceps muscle atrophy persists despite rehabilitation, leading to loss of lower limb strength, osteoarthritis, poor knee joint health and reduced quality of life. However, the molecular mechanisms responsible for these deficits in hypertrophic adaptations within the quadriceps muscle following ACL injury and reconstruction are poorly understood. While resistance exercise training stimulates skeletal muscle hypertrophy, attenuation of these hypertrophic pathways can hinder rehabilitation following ACL injury and reconstruction, and ultimately lead to skeletal muscle atrophy that persists beyond ACL reconstruction, similar to disuse atrophy. Numerous studies have documented beneficial roles of nutritional support, including nutritional supplementation, in maintaining and/or increasing muscle mass. There are three main mechanisms by which nutritional supplementation may attenuate muscle atrophy and promote hypertrophy: (1) by directly affecting muscle protein synthetic machinery; (2) indirectly increasing an individual's ability to work harder; and/or (3) directly affecting satellite cell proliferation and differentiation. We propose that nutritional support may enhance rehabilitative responses to exercise training and positively impact molecular machinery underlying muscle hypertrophy. As one of the fastest growing knee injuries worldwide, a better understanding of the potential mechanisms involved in quadriceps muscle deficits following ACL injury and reconstruction, and potential benefits of nutritional support, are required to help restore quadriceps muscle mass and/or strength. This review discusses our current understanding of the molecular mechanisms involved in muscle hypertrophy and disuse atrophy, and how nutritional supplements may leverage these pathways to maximise recovery from ACL injury and reconstruction.

Fig. 1

Key signalling pathways involved in muscle atrophy and hypertrophy. Resistance exercise training and muscle disuse (e.g. following injury and/or bed rest) stimulate muscle hypertrophy (green arrows) and atrophy (red arrows), respectively, and are dependent on positive and negative regulation of a number of key signalling pathways. Resistance training can increase skeletal muscle hypertrophy by activating the Akt and mTOR signalling pathways via both IGF-1 signalling and mechanical stimulation of cell membrane integrins. Activated mTOR increases muscle protein synthesis by phosphorylating a range of key protein substrates, such as GSK-3β, p70S6K and 4E-BP1. In contrast, muscle disuse results in atrophy by increasing myostatin expression, that in turn, regulates downstream myostatin signalling pathways. Myostatin negatively regulates muscle protein synthesis by inhibiting the Akt pathway, which in turn negatively regulates the mTOR signalling pathway via TSC1/2 and Rheb. Increased myostatin also leads to FOXO translocation to the cell nucleus, increasing transcription of genes involved in muscle protein breakdown. Simultaneously, myostatin signalling inhibits satellite cell proliferation and differentiation by inhibiting MRF4 and activating the Smad2/Smad3 complex, switching on genes involved in muscle wasting and leading to muscle fibrosis. Akt, protein kinase B; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; GDP, guanosine-5′-diphosphate; GTP, guanosine-5′-triphosphate; FAK, focal adhesion kinase; FOXO, forkhead box protein-O; MAFbx, muscle atrophy F-box gene; GSK-3β, glycogen synthase kinase-3 beta; mTOR, mammalian target of rapamycin; MRF4, myogenic regulatory factor-4; MuRF-1, muscle RING-finger protein-1; p70S6K, ribosomal protein S6 kinase beta-1; PI3K, phosphoinositide 3-kinase; Rheb, Ras homolog enriched in brain; Smad, receptor-regulated Smad; TSC, tuberous sclerosis proteins

Fig. 2

Effects of nutritional supplementation on mechanisms underlying muscle hypertrophy. There are three major mechanisms by which nutritional supplements may augment muscle hypertrophy: (1) increasing muscle protein synthesis, (2) increasing the individual’s ability to work harder and (3) increasing satellite cell proliferation and differentiation. Dotted lines indicate mechanisms in which the evidence is less established to date. ADP, adenosine diphosphate; ATP, adenosine triphosphate; mTOR, mammalian target of rapamycin; P, phosphate

Fig. 3

Risk factors for ‘low energy availability’ in injured populations (adapted from Burke et al. 2021). Pathological risk factors (red), intentional but misguided risk factors (orange) and inadvertent risk factors (green)

Fig. 4

Dietary factors that may affect muscle protein synthesis (MPS) under special conditions such as reduced energy availability or anabolic resistance. Protein dose [135], post-exercise protein [239], pre-sleep protein [240], protein spread [241], protein source [242, 243], protein form [–246], intact protein foods [247] and meal versus individual protein foods [248]

Fig. 5

Nutritional supplementation goals complementary to the phases of rehabilitation training. The timeframe for a patient to move through each of the five phases of rehabilitation training following ACL injury is determined by their progress and reaching key milestones. As such, the nutritional requirements of the patient through each phase similarly align with the goals of each phase. Matched nutritional supplementation may enhance patient outcomes through each phase