Knee extensor muscles of active older adults with knee osteoarthritis are smaller and weaker but not more fatigable than healthy older adults: Relevance to physical function

Abstract

Objective

While knee extensor (KE) muscle weakness (lower peak torque or power) is common with knee osteoarthritis (KOA), less is known about muscle fatigue (acute decrement in peak torque or power in response to contractile activity) and its impact on mobility in KOA. The aim of this study was to quantify KE muscle weakness, fatigue and mobility in response to a 30-min treadmill walk (30 MTW) in older adults with and without KOA.

Method

Eighteen KOA (73±3 yr) and 18 healthy (71±3 yr,) participants completed a standardized 30 MTW to induce KE muscle fatigue and changes in mobility (Short Physical Performance Battery scores, SPPB). Peak torque and power (120°/s and 240°/s) were quantified pre- and post-30 MTW. Muscle size (maximal fatfree cross-sectional area; mCSA, cm2) and fat fraction were quantified using MRI, and specific power was calculated as peak muscle power/mCSA (Nm×cm-2). Habitual physical activity was quantified using accelerometry.

Results

Lower KE peak and specific torque and power, SPPB and gait speed in KOA at baseline indicated weaker, smaller, fattier muscles, and compromised mobility compared with healthy adults. Muscle fatigue post-30 MTW was significant but did not differ by group. SPPB scores did not change post-30 MTW in either group.

Conclusion

Older adults with and without KOA experienced KE muscle fatigue in response to a 30 MTW. While KOA were weaker and had lower physical function at baseline, muscle fatigue did not exacerbate these deficits, suggesting that interventions for mobility in individuals with KOA should continue to target muscle atrophy and weakness rather than fatigue.

1. Introduction

Knee osteoarthritis (KOA) is a primary cause of disability among older adults [1]. Muscle weakness, specifically knee extensor (KE) muscle weakness, has been identified as a risk factor for KOA initiation and progression [2,3], and contributes to physical function limitations [4,5]. Thus, KE strength is a common therapeutic target for people with KOA [6,7]. However, some studies report only moderate associations between KE peak torque (i.e., strength) and measures of physical function [4,5], or no differences in KE strength gains between individuals who did or did not experience improvements in self-reported pain and function following an exercise intervention [8]. These studies suggest that other factors may contribute to physical function impairments in this population. Fatigability, defined as a deterioration in physical performance and increased perception of effort with activity [9], is suggested to be a barrier to physical activity participation in KOA [10], and thus may contribute both directly and indirectly (through inactivity) to disability.

KE muscle fatigue (i.e., acute decrement in muscle strength in response to contractile activity) [11] is a proposed contributor to fatigability in healthy older adults [9], as it may exacerbate baseline deficits in strength and thus limit physical function. Dynamometry studies show that older adults typically experience less muscle fatigue than younger adults during maximal isometric contractions, but more fatigue during maximal dynamic contractions at faster velocities [[12], [13], [14]]. Fatigue at faster angular velocities is particularly relevant for tasks such as walking and stair climbing, and may have important implications for overall physical function. Knee extensor power, at moderate and faster velocities, is also a better predictor of both medial knee joint loads and physical function than isometric strength in persons with knee joint pathology [15,16]. In addition to dynamometry studies, there is also robust evidence that, in submaximal activities such as prolonged treadmill walking, healthy older adults develop KE muscle fatigue [17,18]. Muscle fatigue experienced during a submaximal activity is suggested to be greater in individuals with muscle weakness due to the greater relative effort of the muscle to accomplish the task [9]. While there is evidence of both muscle weakness and a greater relative effort of the KE in walking [19], there are limited data on muscle fatigue from submaximal tasks for a KOA population.

While in healthy older adults sarcopenia is the primary source of weakness, in individuals with KOA, muscle atrophy may be accompanied by changes in muscle morphology, including greater fat in the muscle [20], and a reduced ability of the central nervous system to volitionally activate the KE [21]. These factors can lead to a lower specific torque or power [22] in KE muscles for KOA (torque or power per unit muscle) [23,24]. The impact of a lower specific muscle power on muscle fatigue during functional tasks has received little attention to date. In KOA, joint pain may also contribute to activation deficits [25], as acute flares in pain during walking may exacerbate activation failure and thus muscle fatigue. Evidence to explain whether and how muscle weakness and reduced specific torque may impact muscle fatigue and exacerbate physical function impairments in KOA is limited. A greater understanding of muscle fatigue in KOA is needed as fatigue may also have a substantial impact on habitual physical activity, a key behavior for OA management.

To date, there is limited information about muscle fatigue and its impact on physical function in KOA. The first aim of this study was to quantify KE muscle fatigue in response to an acute bout of treadmill walking in older adults with and without KOA. We hypothesized that KOA would have greater muscle fatigue than healthy controls and that this fatigue would be exacerbated in those with lower KE specific power. The second aim was to compare KOA versus healthy controls, with respect to the impact of muscle fatigue from the 30-min treadmill walk (30 MTW) on physical function. We hypothesized that KE muscle fatigue would have a negative association with physical function in KOA compared with healthy controls.

2. Methods

2.1. Participants

Thirty-six older adults participated in this study, 18 with symptomatic KOA and 18 older healthy (OH) adults. All participants provided both University of Massachusetts' Institutional Review Board approved informed consent and health care provider consent. Participants were recruited via social media, word of mouth, direct mailings, newspaper ads, flyers and community outreach programs, gyms, hospitals, outpatient clinics, and a campus-wide, IRB-approved volunteer database. Our sample size afforded ample power (>80%) to declare as statistically significant observed differences in mean muscle power as small as ∼12.9 Nm (representing an approximately 10–17% difference detectable) across two groups when performing a two-sided t-test with r type I error = 0.05 [26].

OH participants were aged 70–80 years, ambulatory and able to walk unaided, living independently in the community, and able to pass the Physical Activity Readiness Questionnaire for Everyone [27]. KOA participants were included if they were between 65 and 80 years of age, currently experiencing knee pain, and met at least two of the following three criteria: a physician's diagnosis of KOA, Kellgren-Lawrence score of 2–3, Knee Osteoarthritis Outcome Score (KOOS) pain score of ≤70 [28]. If a participant had bilateral KOA, the more symptomatic limb was used for analysis. KOA participants were excluded for the following: recent knee injection, joint replacement, other conditions affecting lower limb function. Participants in both groups were also excluded for the following: inability to walk unaided by an orthopedic or prosthetic device, history of cardiovascular disease, neurological disorders such as Parkinson's disease, multiple sclerosis or stroke, or high tibial osteotomy.

2.2. Data collection

Participants completed two study visits 7–10 days apart to facilitate measurement of habitual physical activity. At Visit one, after providing informed consent, participants completed the following: questionnaires, MRI (magnetic resonance imaging), habituation to study procedures (dynamometer, treadmill walking), habitual gait speed assessment, and physical activity monitor assignment. At Visit two, participants completed the following pre and post 30-min treadmill walk (30 MTW): gait analysis, dynamometry for KE peak torque and power.

2.3. Physical activity

All participants wore a triaxial accelerometer (GT3X, Actigraph, Pensacola, FL) on the hip for a minimum of seven days following Visit one. Weekly minutes of moderate to vigorous physical activity (MVPA) were calculated using established cut points based on a minimum of four days of at least 10 h of wear time including one weekend day, as described previously [29].

2.4. 30-Minute treadmill walk

Participants completed a 30 MTW at their preferred speed, as described previously [17]. Preferred speed was determined using timing gates as participants walked across a 6 m walkway at preferred speed with a 3 m acceleration and deceleration zone before and after the gates [30]. The treadmill speed was gradually increased until it reached the preferred speed, and participants were asked if they felt they could maintain this speed for 30 min. If the participant could not maintain this speed, speed was decreased in 0.1 mile/hr increments until they reached a speed they felt confident they could maintain. At minutes 7, 14, and 20, a 1-min 3% incline challenge was implemented.

2.5. Dynamometry

Maximal KE muscle torque and power were measured using an isokinetic dynamometer (Biodex System 4 Pro, Shirley, NY) before and after the 30 MTW. Participants were seated with the hip flexed to 90°. For isometric testing, the knee was flexed to 70° and for isokinetic testing the joint moved through a 70-degree range of motion from 80 to 10° of flexion at 120 or 240° per second (°/s). Participants completed a standardized warm up protocol of 1–3 contractions at 25%, 50%, 75%, and at 100% of peak torque. Verbal encouragement was given during all maximal contractions. At baseline, two sets of three repetitions of maximal voluntary isometric contractions (MVIC) were completed with five seconds of rest between reps and two minutes of rest between sets. For the maximal isokinetic contractions, one set of three repetitions at each speed was completed, with two minutes of rest between contraction speeds. Post 30 MTW, no rest was given between repetitions or sets to limit recovery from fatigue and only one repetition of the isometric knee extension was completed in addition to all isokinetic contractions. Maximum torque values at the target velocity were extracted for all contractions. Peak muscle power was calculated as the product of peak torque and the corresponding velocity observed at that time. Torque and power data were normalized to body mass (kg) to account for differences in body size between participants.

2.6. Rating of perceived exertion (RPE)

Ratings of perceived exertion were quantified using the modified Borg scale CR10 [31] of effort in response to the question “how hard are you working at this moment” (range 0 = 10; 0 = “nothing at all,” 10 = “very, very strong/almost max”). RPE was measured during quiet standing prior to the start of the 30 MTW and then every 6 min throughout the treadmill walk. The difference between baseline and final RPE was recorded.

2.7. Verbal numeric rating scale for pain

For KOA participants, pain was assessed using a verbal numeric rating scale (vNRS, range 0–10 points) where 0 = “no pain at all” and 10 = “pain as bad as it could be” [32] and measured before and every five minutes throughout the treadmill walk. The pain scores in the first and final minute of the 30 MTW were used to evaluate acute changes in pain in response to the treadmill walk.

2.8. Advanced Short Physical Performance Battery (SPPB-A)

To assess physical function, participants completed the “advanced” Short Physical Performance Battery (SPPB-A) [33] which includes balance tasks, walking and chair rises. The SPPB-A includes a 6 m walk; 6 m balance walk; 30s balance tests in the side-by-side, semi-tandem, tandem and single leg stances; and five rapid repeated chair rises. The SPPB-A contains similar activities as the standard SPPB test but extends the time for the balance tests to 30 s and includes a single leg stance [33] to allow for the differentiation of functional capacity in higher-functioning older adults. The SPPB-A is scored on a scale from 0 to 4 with each subcomponent contributing a maximum of one point to the total score.

2.9. Muscle morphology

Axial images of the thigh were obtained in a 3 T MRI system using a multi-echo (6-point) fat-water “Dixon” sequence (three stacks, 8 mm slice thickness, 24 slices per stack, TR = 35 ms, voxel volume: 1.25 × 1.25 × 8). A region of interest was drawn around the KE muscle group on each slice [34,35]. Peak fat-free muscle cross-sectional area (mCSA, cm²) and fat fraction (%) were quantified using a custom-written MATLAB script (MathWorks, Natick, MA). Specific torque and power were calculated as the ratio of peak isometric torque or power at 120 and 240°/s to mCSA.

2.10. Cartilage morphology

Images of the knee joint were obtained using a 3-dimensional Dual Echo Steady State sequence for KOA participants [36]. The cartilage damage index (CDI) was used to quantify structural severity in KOA participants (see supplementary methods for all specific method details) [37].

2.11. Primary outcomes and predictor variables

In our main analyses, comparing KOA versus healthy controls with respect to KE muscle fatigue responses to treadmill walking and the physical function consequences of muscle fatigue, our primary predictor was group at two levels, KOA versus healthy control modeled using a 0/1 indicator of KOA with healthy control as the referent. Analyses of group differences in KE muscle fatigue responses to treadmill walking considered three primary outcomes: peak KE torque, KE power at 120°/s (W/kg) and 240°/s (W/kg). Analyses of group differences in physical function consequences of muscle fatigue considered one primary outcome, SPPB-A score.

2.12. Covariates

We also measured several covariates, including biological sex, age, height, mass, gait speed, weekly MVPA, mCSA, and fat fraction. These data were used to describe our study sample and in ancillary analyses to investigate biological sex and specific power at baseline as potential confounders or modifiers of our main analysis findings. While these analyses were not powered for formal tests of significance, of particular interest here were explorations of biological sex as both a confounder and a modifier of group differences (KOA versus healthy controls) in KE muscle fatigue and SPPB-A outcomes.

2.13. Statistical analyses

We computed descriptives of our study sample separately for KOA and healthy controls using means and standard deviations (SD) to evaluate group differences at baseline. Two-sample t-tests of equality of group means were performed as appropriate. In our main analyses, we analyzed KE muscle fatigue responses to the 30 MTW using linear mixed effects modeling, with group and subject modeled as fixed and random effects, respectively. Separate models were estimated for each of our primary outcomes (peak KE torque, KE power at 120°/s (W/kg) and 240°/s (W/kg), and SPPB-A score). For each outcome, we fit a three-predictor model that included as predictors the following: 0/1 indicator of KOA, occasion and KOA × occasion interaction. This yielded linear mixed models that are equivalent to 2 (group) x 2 (occasion) mixed model analyses of variance. For each outcome, we tested the null hypothesis of zero KOA × occasion interaction to assess whether KOA, relative to healthy control, is associated with a statistically significant different response to the 30 MTW.

Linear regression was used to assess the associations between KE fatigue (change in torque % initial) and the change in physical function (ΔSPPB-A score) and their variation by group. The change in torque was expressed as % initial (post/pre x 100). To assess the relationship between specific power and fatigue (change in MVIC, % initial) we modeled the dependent variable change in torque in relationship to three predictors: 0/1 indicator of KOA group, specific power (Watts/cm²) at baseline, and the interaction KOA x baseline specific power.

For all outcomes, we confirmed the appropriateness of the assumption of normality of outcome distribution using scatterplots and tests of the null hypothesis of normality (data not shown). R v4.1.2 was used for all statistical analyses.

3. Results

3.1. Baseline

Descriptives of the study cohort and their characteristics at baseline are shown in Table 1. KOA were younger, heavier and had a higher BMI compared with OH. Gait speed and MVPA were not different between groups (p ≥ 0.05, both). Maximal mCSA was not different by group (p = 0.846), but there was a significant sex difference (p < 0.001). Compared with females, mean mCSA was 18.9 cm² greater in males. We observed group differences in fat fraction (p = 0.005) but no differences by sex (p = 0.10). Knee extensor peak torque (p = 0.014) and power at 120°/s (p = 0.005) and 240°/s (p < 0.001) were lower in KOA than OH (Supplementary Figure 1, Table 1). At both 120°/s and 240°/s, males were stronger than females (power at 120°/s p = 0.005; power at 240°/s p < 0.001). Group differences in KE peak torque, KE peak power at 120°/s (p = 0.09) and KE peak power at 240°/s were similar in males and females. Specific torque (p = 0.009) and power at both 120°/s (p < 0.001) and 240°/s (p < 0.001) were also lower in KOA than OH. KOA had a lower physical function than OH based on the total SPPB-A score (p < 0.001, Fig. 1).

Table 1.

Baseline group characteristics; mean (SD).

Measure	OH (n = 18) (9 female)	KOA (n = 18) (9 female)	P value	Effect Size
Age (years)	73 (3.3)	71 (3.5) ∗	0.003	0.912
Height (m)	1.71 (0.09)	1.71 (0.11)	0.475	0.020
Mass (kg)	70.3 (11.5)	79.5 (15.4) ∗	0.023	0.659
BMI (kg/m2)	23.8 (2.86)	26.9 (3.79) ∗	0.003	0.915
Gait speed (m/s)	1.35 (0.09)	1.28 (0.18)	0.088	0.440
Weekly MVPA (min)	300 (153)	240 (176)	0.858	0.354
mCSA (cm2)	50.1 (14.4)	49.4 (9.66)	0.557	0.048
Fat fraction (%)	7.42 (1.50)	9.99 (3.05) ∗	0.002	1.045
Peak KE MVIC (Nm/kg)	2.22 (0.62)	1.73 (0.49) ∗	<0.001	0.869
Peak KE power @120°/s (W/kg)	2.75 (1.02)	1.80 (0.485) ∗	<0.001	1.158
Peak KE power @240°/s (W/kg)	4.44 (1.54)	2.52 (0.82) ∗	<0.001	1.579
Specific torque (Nm/cm2)	3.19 (0.49)	2.79 (0.45) ∗	0.009	0.826
Specific power 120°/s (Watts/cm2)	3.90 (0.97)	2.92 (0.63) ∗	<0.001	1.173
Specific power 240°/s (Watts/cm2)	5.62 (1.61)	3.85 (0.79) ∗	<0.001	1.405
SPPB-A score	2.6 (0.35)	2.1 (0.39) ∗	<0.001	1.290
KOOS pain	98.4 (4.5)	69.5 (11) ∗	<0.001	3.22
KOOS ADL	98.6 (4.4)	77.5 (13.7) ∗	<0.001	2.051
Medial femur CDI	–	617 (415)
Lateral femur CDI	–	1048 (385)
Medial tibia CDI	–	284 (238)
Lateral tibia CDI	–	417 (273)

OH = older healthy, KOA-knee osteoarthritis; KOOS= Knee Osteoarthritis Outcome Score (scale of 0–100, with zero representing extreme knee problems); CDI = cartilage damage index, lower score indicates more cartilage damage; P-values are for two sample t-test; Effect size = Cohen's d = (KOA mean - OH mean)/(pooled SD).

Fig. 1.

Baseline advanced SPPB score was lower in KOA than OH. Data are presented by group and sex (red diamond = mean), # indicates group difference in SPPB-A score.

At baseline, all participants were able to complete isokinetic KE contractions at 120 and 240°/s. However, post 30 MTW only 15/18 individuals with KOA were able to achieve the target velocity of 120°/s and only 14/18 KOA and 16/18 OH were able to achieve the target velocity of 240°/s (Fig. 2). Therefore, analyses of pre-to post changes in torque and power considered only those participants who achieved their target velocities post 30 MTW.

Fig. 2.

Number of participants in the KOA (top row) and OH (bottom row) that could achieve the target velocity for each condition: MVIC (0° or isometric, 120°, 240°).

3.2. Post-30 MTW

KE MVIC (p < 0.001), and KE power at 120°/s (p = 0.005) and 240°/s (p = 0.05) all decreased in both groups post 30 MTW, Fig. 3. The average change in pain for KOA with the 30 MTW was 1.5 ± 1.6 points (p = 0.002). The change in RPE from pre to post 30 MTW was 1.22 ± 1.6 (p = 0.50) in KOA and 1.75 ± 0.98 in OH (p < 0.001) indicating that only the OH group had a significant increase in RPE.

Fig. 3.

Knee extensor peak torque and power pre and post 30 MTW in OH and KOA. Data and box plots, by group and time (grey diamond = mean). MVIC (left), peak power at 120°/s (center), and peak power at 240°/s in older healthy and knee osteoarthritis groups.

The decline in MVIC did not differ by group (p = 0.88). MVIC after the 30 MTW 85.8% (14.5) of initial for KOA and 85.2% (1.01) of initial for OH. The change in muscle power also did not differ by group (120°/s p = 0.13; 240°/s p = 0.88). Peak power at 120°/s was 89.7 % (13.8) of initial in KOA and 96.7 % (10.8) of initial for OH after the 30 MTW. Peak power at 240°/s was 96.1% (15.8) of initial for KOA and 96.8 % (9.35) of initial for OH after the 30 MTW (Fig. 3).

Linear regression modeling of specific power (120°/s) and fatigue (change in MVIC, % initial) that considered group (0/1 indicator of KOA), baseline specific power, and the interaction group x baseline specific power yielded no model that significantly predicted fatigue (p > 0.05; Table 2).

Table 2.

Estimated change (Beta, 95% CI) in specific power response (% Initial) to 30 MTW: Multiple predictor regression analysis (n = 34). Model 1 single predictor model with group, Model 2 single predictor model with specific power, Model 3 two predictor model with group and specific power, and Model 4 three predictor model with group, specific power, and interaction of group and specific power. There was no model that significantly predicted fatigue (all p > 0.05).

	Model 1 Beta (95% CI)	Model 2 Beta (95% CI)	Model 3 Beta (95% CI)	Model 4 Beta (95% CI)
KOA (ref = OH)	0.38 (−8.25, 9.00)		2.84 (−7.34, 13.01)	2.20 (−38.07, 42.47)
Specific power (Watts/cm2)		1.70 (−2.87, 6.26)	2.49 (−2.94, 7.93)	2.44 (−4.13, 9.00)
Interaction: KOA ∗ specific power				0.20 (−11.95, 12.35)

KOA – knee osteoarthritis, OH – older healthy.

Linear regression modeling of differences in KE fatigue (change in torque % initial) and the change in SPPB-A score found that fatigue did not predict change in physical function (β = −2.13, 95% CI: (−18.3, 14.01).

4. Discussion

The purpose of this study was to quantify KE muscle fatigue and understand the consequences of KE fatigue on physical function in individuals with and without KOA. Individuals with KOA were weaker than older healthy and physical function was lower in KOA. There was no impact of muscle fatigue on physical function based on the change in total SPPB-A score. There was also no association between muscle fatigue and changes in physical function in response to the 30 MTW. Our results suggest that in active adults with KOA, muscle fatigue does not impact physical function and other factors such as muscle strength or maintenance of active lifestyles should be prioritized to limit reductions in physical function.

In response to the prolonged treadmill walk, participants in both groups experienced muscle fatigue based on the changes in KE peak isometric torque, and power at both 120 and 240°/s (Fig. 3). The magnitude of muscle fatigue resulting from the 30 MTW was similar to prior work in sedentary older women [17] and low-active midlife adults [18] for isometric torque (MVIC), and power at 120°/s. Although significant, at 240°/s the change in KE power following the 30 MTW was small in both groups relative to other studies [17,18]. This smaller amount of fatigue at 240°/s than observed previously may be due in part to the fact that four KOA and two OH were unable to achieve the target velocity of 240°/s following the 30 MTW (Fig. 2). It was not possible to calculate KE muscle power for these individuals due to the absence of an isovelocity phase during the contraction, a primary requirement for determining peak torque and power using dynamometry. Thus, our reported fatigue at 240°/s is likely an underestimation as we were not able to include data from those who likely fatigued the most at that velocity. An inability of older adults to hit a target velocity has been hypothesized to be due to age-rated slowing of contraction speed as a result of changes in muscle function with age or fatigue [38]. In addition, recent work suggests that the KE muscle fascicles may undergo very little length change (i.e., near-isometric contractions) during the period of highest loading during gait [39,40]. As such, the isometric loading during the 30 MTW may have been relatively greater than for the dynamic contractions, yielding greater fatigue in that condition. However, the smaller relative differences in muscle power at the highest velocity may be an artifact of our approach.

The initial hypothesis that KOA would experience greater muscle fatigue than OH stemmed from the expected greater relative muscular effort required to walk [19,41] due to smaller absolute and specific KE torques. However, no differences were found in KE muscle fatigue between KOA and OH. At baseline, results did indicate that the KE were weaker, smaller, fattier muscles in KOA compared with healthy adults. However, the average peak torque in the KOA group was 167 ± 48 Nm for males and 114 ± 26 Nm for females, which are at the high end of the range of values reported in the literature for peak KE torque with KOA (males-131 ± 43 Nm and females 76 ± 26) [42]. The average KE power at 240°/s for both males and females were slightly lower than what has been reported in the literature previously for females with KOA (3.25 Nm/kg) [26]. The higher isometric KE peaks and similar dynamic peaks suggest the KOA group may only be experiencing mild KE weakness compared with prior reports on individuals with KOA. This may be related to the physical activity patterns of the participants. Some studies report that individuals with KOA do not achieve recommended levels for moderate or greater intensity physical activity [43]. However, the KOA group in this study had an average MVPA of 240 min per week, with only two participants not exceeding the recommended 150 min per week [44], indicating that our KOA study cohort was rather active. As a result, the habitual physical activity of the individuals with KOA in this study may have influenced the impact of KOA on their KE function.

The lack of group difference in KE fatigue may have also been a result of a lower ability to activate the KE muscles. A study of KOA patients found that, after repeated isometric contractions, muscle fatigue in KOA was less in the affected limb than the unaffected limb [45]. The lower fatigue in the affected limb was due to an inability to produce the maximal torque due to central activation failure, also known as atherogenic muscle inhibition [45]. Baseline specific torque and power were significantly lower in KOA compared with OH, while maximal cross-sectional area did not differ. A lower specific torque or power with no difference in cross-sectional area indicates an impairment in the ability to fully activate the muscle (i.e., central activation deficits) or intramyocellular contractile failure. However, in the present study there was no relationship between specific power and muscle fatigue, indicating that other factors, such as differences in gait mechanics, may be the primary determinant of muscle fatigue in walking in this population. Further research is needed to better understand the role of central activation failure or poor muscle contractile function in KOA, and how this may impact KE fatigue.

KE muscle fatigue did not predict a change in physical function following the 30 MTW. At baseline, the KOA group had lower physical function, based on the SPPB-A scores. This was expected as prior work has found that individuals with KOA report six times greater physical function limitations than age- and sex-matched controls [46]. The KE muscle fat fraction was higher in our KOA group, and greater intramuscular fat in combination with KE weakness may be a contributing factor to lower physical function in KOA [47]. However, the observed changes (0.05 in KOA and 0.01 in OH) in SPPB-A score pre-to post 30 MTW were smaller than the clinically meaningful change of 0.12 points [48]. The lack of change in physical function with KE fatigue observed may be due to the relatively mild KE weakness at baseline for KOA and the robust physical activity patterns for both groups, with weekly MVPA that exceeded what is commonly reported in the literature for both individuals with KOA and OH [49]. Overall, despite experiencing KE muscle fatigue, our KOA participants may have had an ample functional reserve to maintain performance on the functional tasks.

It is important to interpret the results of our study, specifically the similar KE muscle fatigue with a prolonged walk for KOA and OH and a lack of impact of KE fatigue on physical function, within the context of the participant characteristics. KOA structural severity was quantified with the Cartilage Damage Index (CDI) [37]. The average CDI for the medial tibia and femur (Table 1) indicated the KOA group had moderate to severe medial compartment KOA, similar to a Kellgren and Lawrence grade 3 for radiographic OA [37]. The individuals with KOA were also experiencing moderate symptomatic disease based on the overall, pain, and activities of daily living subscores on the KOOS. They also tended to experience a clinically significant acute flare in joint pain with the 30 MTW [50], indicating symptoms sensitive to mechanical loading. However, while the SPPB-A score indicated that KOA had lower overall physical function at baseline, their “normal” preferred walking speed and physical activity patterns suggest that this group was not experiencing substantial deficits in overall physical function. Therefore, these study findings may not transfer to less active individuals with KOA. It will be important to evaluate the relationship between KE fatigue and physical function in low-active KOA participants, as this may provide new insight regarding potential therapeutic interventions in this segment of the population.

Few studies quantify knee extensor fatigue in individuals with KOA, particularly using a whole-body exercise task. Knee extensor muscle fatigue has important clinical implications due to the key role of extensor muscles for activities of daily living, especially in a population with muscle weakness such as KOA. The results of this study suggest that, despite KE weakness, lower physical function at baseline, and pain with the 30 MTW, individuals with moderate symptomatic KOA do not fatigue more than OH during 30 min of walking at their preferred speed. This apparent resistance to muscle fatigue in KOA may be due in part to the relatively high MVPA of our groups, but could also be due to a lower demand on the knee extensor muscles due to KOA-based gait adaptations. These results suggest that interventions designed to preserve physical function in individuals with KOA should continue to target muscle atrophy and weakness.

Author contribution

All authors contributed to study conception and design. Dr. Holmes performed the collection and analysis of data. All authors contributed to the interpretation of the data, manuscript drafting and revision, and approved of the submitted version.

Funding source

Dr. Holmes was supported by a National Institute on Aging (NIA) grant (F31 AG079538), International Society of Biomechanics Matching Dissertation Grant, and a University of Massachusetts Graduate School Dissertation Grant. Data from Dr. Boyer's NIA grant (R01 AG068102) were used for the control group.

Declaration of competing interest

The authors declare no competing interests.

Handling Editor: Professor H Madry

Appendix A. Supplementary data

The following is the supplementary data to this article: