Abstract
IntroductionDespite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness. Derangements in mitochondrial function are a common feature of various atrophying conditions, yet it is unclear to what extent mitochondria are involved in the detrimental sequela of quadriceps dysfunction after ACL injury. Using a preclinical, non-invasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on mitochondrial function, muscle atrophy, and muscle phenotypic transitions.MethodsA total of 40 male and female, Long Evans rats (16-week-old) were exposed to non-invasive ACL injury, while 8 additional rats served as controls. Rats were euthanized at 3, 7, 14, 28, and 56 days after ACL injury, and vastus lateralis muscles were extracted to measure the mitochondrial respiratory control ratio (RCR; state 3 respiration/state 4 respiration), mitochondrial reactive oxygen species (ROS) production, fiber cross sectional area (CSA), and fiber phenotyping. Alterations in mitochondrial function and ROS production were detected using two-way (sex:group) analyses of variance. To determine if mitochondrial characteristics were related to fiber atrophy, individual linear mixed effect models were run by sex.ResultsMitochondria-derived ROS increased from days 7 to 56 after ACL injury (30–100%, P < 0.05), concomitant with a twofold reduction in RCR (P < 0.05). Post-injury, male rats displayed decreases in fiber CSA (days 7, 14, 56; P < 0.05), loss of IIa fibers (day 7; P < 0.05), and an increase in IIb fibers (day 7; P < 0.05), while females displayed no changes in CSA or phenotyping (P > 0.05). Males displayed a positive relationship between state 3 respiration and CSA at days 14 and 56 (P < 0.05), while females only displayed a similar trend at day 14 (P = 0.05).ConclusionLong-lasting impairments in quadriceps mitochondrial health are present after ACL injury and play a key role in the dysregulation of quadriceps muscle size and composition. Our preclinical data indicate that using mitoprotective therapies may be a potential therapeutic strategy to mitigate alterations in muscle size and characteristic after ACL injury.
Highlights
Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness
A longitudinal reduction in mitochondrial respiratory control ratio (RCR) was found to be present in conjunction with a longitudinal increase in reactive oxygen species (ROS) production after ACL injury
ROS production was significantly elevated compared to controls in all ACL injury groups in males (control: 9.72 ± 0.74 pmol mg−1 min−1; day 3: 12.81 ± 1.84 pmol mg−1 min−1, mean difference = 3.09, P = 0.04, 95% CI: 0.16, 6.02, d = 2.20; day 7: 14.16 ± 1.67 pmol mg−1 min−1, FIGURE 1 | Mitochondrial function following non-invasive ACL injury. (A–D) Mitochondria respiratory function and ROS production
Summary
Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness. Derangements in mitochondrial function are a common feature of various atrophying conditions, yet it is unclear to what extent mitochondria are involved in the detrimental sequela of quadriceps dysfunction after ACL injury. Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term muscle weakness (Lepley, 2015; Otzel et al, 2015; Cinque et al, 2017). The extent to which mitochondria are involved in the detrimental sequela of quadriceps muscle after ACL injury is not well understood. Muscle phenotypic transitions that occur after ACL injury may be closely linked with mitochondrial health (Babcock et al, 2015; Noehren et al, 2016)
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