Locomotor activity and gait in aged mice deficient for type IX collagen

Abstract

Osteoarthritis (OA) is a risk factor for physical inactivity and impaired mobility, but it is not well understood how these locomotor behaviors are affected by the age of onset of OA and disease severity. Male mice homozygous for a Col9a1 gene inactivation (Col9a1(-/-)) develop early onset knee OA, increased tactile pain sensitivity, and gait alterations by 9 mo of age. We hypothesized that aged Col9a1(-/-) mice would reduce joint pain by adopting locomotor behaviors that reduce both the magnitude and daily frequency of joint loading. We tested this hypothesis by evaluating gait and spontaneous locomotor activity in 15- to 17-mo-old male Col9a1(-/-) (n = 5) and Col9a1(+/+)(WT) (n = 5) mice using well-controlled measures of voluntary activity in overground and running wheel conditions, as well as studies of gait in a velocity-controlled treadmill. We found no difference due to genotype in freely chosen locomotor velocity, stride frequency, hindfoot duty factor, dark phase activity time, or dark-phase travel distance during overground, running wheel, or speed-matched treadmill locomotion. Interpretation of these findings is potentially confounded by the observation that WT mice have greater knee OA than Col9a1(-/-) mice in the lateral tibial plateau by 17 mo of age. When accounting for individual differences in knee OA, functional locomotor impairments in aged Col9a1(-/-) and WT mice are manifested as reductions in total locomotor activity levels (e.g., both distance traveled and time active), particularly for wheel running. These results support the concept that current disease status, rather than age of disease onset, is the primary determinant of impaired locomotor activity with aging.

Fig. 1.

Sagittal sections of the femoral and tibial articular surfaces from 17-mo-old wild-type (WT) and Col9a1^−/− mice. Representative sections are shown for the medial (A) and lateral (B) compartments of the knee. A: in the medial compartment, Col9a1^−/− mice have significant cartilage loss, whereas, only mild superficial fibrilation is observed in WT mice. B: in the lateral compartment, both Col9a1^−/− and WT mice show minor cartilage structural changes and loss of Safranin-O staining. Sections were stained with hematoxylin, fast green, and Safranin-O. Images are ×200 magnification (scale bars = 100 μm).

Fig. 2.

Histomorphometric knee osteoarthritis (OA) scores for 17-mo-old Col9a1^−/− mice and WT mice. A: modified Mankin OA score, expressed as a percent of the maximum score, for each graded site in the knee joint. Col9a1^−/− scores were significantly greater than WT scores in the medial femur and lower in the lateral tibia. B: cartilage structural degeneration score, a subcomponent of the Modified Mankin score, for each graded site in the knee joint. Col9a1^−/− mice had significantly greater cartilage degeneration than WT mice in the medial compartment, while there was no significant difference in degeneration in the lateral compartment. Values are means ± SE.

Fig. 3.

Kinematics of locomotion related to the magnitude of ground force generation. Freely chosen average speeds over a 72-h time period for “open field” overground locomotion (A) and wheel running (B). Spontaneous wheel running speeds were significantly faster than those used overground and tended to be slower in Col9a1^−/− mice. C: hindlimb duty factors during speed-matched treadmill locomotion were not significantly different between Col9a1^−/− mice and WT mice. D: hindlimb duty factors during voluntary wheel running were not significantly different between Col9a1^−/− and WT mice. Duty factors were compared at 10 cm/s for both Col9a1^−/− and WT mice from strides collected at the beginning of the dark cycle. Values are means ± SE.

Fig. 4.

Spontaneous overground locomotor behavior and treadmill kinematics related to the frequency of joint loading. A: no significant differences were observed between Col9a1^−/− and WT mice in the pattern of spontaneous overground activity averaged over a 72-h time period. Data are plotted for the total distance moved for each half hour of the day (bar beneath the plot indicates the light/dark periods). B: Col9a1^−/− mice moved slightly shorter distances during the dark cycle compared with WT mice, although this difference was not significant. C: there was also a nonsignificant trend for reduced activity time, expressed as a percent of the dark period, in Col9a1^−/− mice compared with WT mice. D: stride frequencies recorded during speed-matched treadmill locomotion were not significantly altered in Col9a1^−/− mice. Values are means ± SE.

Fig. 5.

Spontaneous wheel running behavior and kinematics related to the frequency of joint loading. A: WT mice showed increase wheel running activity during the first half of the dark cycle compared with Col9a1^−/− mice, but there was no difference in wheel activity during the second half of the dark cycle. Average data for a 72-h time period are plotted for the total distance moved for each half hour of the day (bar beneath the plot indicates the light/dark periods). B: Col9a1^−/− mice ran shorter distances during the dark cycle compared with WT mice, although this difference was not significant. C: there was also a nonsignificant trend for reduced activity time, expressed as a percent of the dark period, in Col9a1^−/− mice compared with WT mice. D: stride frequencies recorded during approximately speed-matched wheel locomotion were similar in Col9a1^−/− and WT mice. Values are means ± SE.