Mechanisms underlying the age-related changes in muscle contractile properties

Ramos, Jorgelina (2016) Mechanisms underlying the age-related changes in muscle contractile properties. Doctoral thesis (PhD), Manchester Metropolitan University and KU Leuven.

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Abstract

Changes in isometric fore and power output in old age have been extensively studied for but less attention has been paid to eccentric contractions where, paradoxically, there are suggestions that eccentric strength is maintained with ageing. Decreased isometric force and relatively increased eccentric strength are feature of permeabilised single fibres developed in the presence of high inorganic phosphate (Pi) and it is possible that there may be a connection between the changes in contractile function seen with ageing and the actions of Pi. The work described in this thesis involved mouse soleus fibres and had two major aims. The first was to understand more about the nature of the response to stretch and the role of Pi, especially concerning the rate of stress relaxation which may provide information about cross bridge kinetics. The second aim was to study to what extent changes in cross bridge function account for the age related changes in contractile characteristics. In the first study, three features of the force response to stretch, peak force at the end of the ramp stretch, the stress relaxation and the residual force enhancement were observed in young mouse single fibres at different velocities of stretch. Stress relaxation was analysed as a double exponential decay with a constant component, force enhancement (FE). The speed of the fast exponential component increased with speed of stretch and the proportions of the fast component (A2) relative to the slow component (A1) also increased with speed of stretch. FE was independent of speed. Addition of Pi slowed stress relaxation and increased the proportion of the slow component. One explanation is that the slow component represents the detachment of attached cross bridge states that generate little or no force while the fast component is due to detachment of cross bridges in a high force state. FE is probably due to stretching of a series compliance such as titin. The response to stretch varied with age in complex ways. In mice aged 3, 10 and 18-month-old there were small but non-significant increases in the force sustained during stretch relative to the isometric force together with a similar stress relaxation. However, with 32-month-old fibres the stress relaxation was faster than seen with young fibres consistent with an increase in the proportion of the fast A2 cross bridge intermediate state. Adding Pi to the oldest fibres changed the proportions of A1 and A2 to those seen in young fibres in the absence of Pi. The results largely contradict previous reports of the relative preservation of eccentric force with age, which may be due to simple change in fibre type composition of whole muscles, but do indicate possible changes in cross bridge kinetics affecting the transition from low to high force states.