Initiating exercise training in late middle age minimally protects muscle contractile function and increases myocyte oxidative damage in senescent rats

Abstract

Age-related loss of muscle mass and function exhibits a marked acceleration from late middle age to senescence and exercise training is one method that has been proposed to slow this process. The purpose of this study was to determine if long-term treadmill exercise training initiated at late middle age could increase endogenous antioxidant enzyme activity and attenuate the loss of skeletal muscle contractile properties in the gastrocnemius/plantaris (GAS/Plan) and soleus (SOL) muscles of senescent rats (34–36 mo) through a decrease in oxidative damage. Male Fisher 344 × Brown Norway F1-hybrid rats underwent 5–7 mo of treadmill training beginning at late middle age (29 mo). A 7 mo sedentary adult group was used to investigate age-related changes. Aging caused an increase in antioxidant enzyme activities; however, only SOD activity was further increased with exercise training. Exercise training did not attenuate the decrease in twitch or tetanic tension of the GAS/Plan or SOL. It did, however, prevent the increase in twitch half relaxation time of the SOL muscle only. Oxidative damage, as reflected in carbonyl content, was increased with age and even further with exercise training in the GAS muscle. Muscle fibre cross sectional area was decreased with age and even further with exercise training. Interestingly, small muscle fibres showed the highest accumulation of carbonyls. Overall, despite an augmentation of select antioxidant enzyme activities, exercise training from late middle age through to senescence had minimal benefits for muscle contractile properties, perhaps in part due to exacerbated oxidation.

Introduction

Sarcopenia refers to the decrease in muscle mass and function that occurs with normal aging (Doherty, 2001). The loss of muscle strength with aging exceeds that which can be accounted for by the loss of muscle mass and is evident when force is normalized to muscle mass (Brown and Hasser, 1996, Hepple et al., 2005) or muscle cross sectional area (i.e., a reduced specific force) (Akima et al., 2001, Brooks and Faulkner, 1988, Mayhew et al., 1998). Strikingly, it is even apparent at the single fibre level (Thompson and Brown, 1999), suggesting intrinsic changes within muscle fibres contribute to the specific force decline with aging.

In line with the free radical theory of aging proposed by Harman (1956), reactive oxygen species-induced damage has been hypothesized to be one of the mechanisms causing sarcopenia (Fulle et al., 2004) and may play an important role in impairing skeletal muscle function. Consistent with this view, aged skeletal muscle has greater oxidative damage to proteins, lipids and DNA (Fano et al., 2001, Ji et al., 1990, Mecocci et al., 1999). Furthermore, several studies have documented increases in oxidative damage in skeletal muscles of aged rats (Hepple et al., 2008, Kaldor and Min, 1975, Srivastava and Kanungo, 1982), increased levels of serum protein carbonyls correlate with poor grip strength in older women (Howard et al., 2007), and impaired function of meromyosin in aged muscle correlates with a reduced number of reactive cysteines due to oxidative damage (Prochniewicz et al., 2005). It seems reasonable, therefore, to suggest that if protein oxidative damage could be reduced, the age-related decline in muscle function may be attenuated. This latter hypothesis is supported by our previous observation that the protection of contractile and aerobic function in senescent muscles by caloric restriction (Hepple et al., 2005) is associated with an abrogation of the age-related increase in muscle protein oxidative damage (Hepple et al., 2008).

While caloric restriction is a useful model for examining mechanisms by which muscle may be protected with aging, it is not a very practical intervention. Moderate treadmill exercise training, on the other hand, is both practical and increases the activity of endogenous antioxidant enzymes (Hammeren et al., 1992, Ji et al., 1991) which may also facilitate protection from oxidative damage with aging (Goto et al., 2004, Ji, 2002). The impact of exercise training on antioxidant activity in old animals are not conclusive, with some studies reporting increases in the activity of some endogenous antioxidants (Ji et al., 1991), while others show no effect (Leeuwenburgh et al., 1994) and even decreases in antioxidant activities (Lambertucci et al., 2007). Irrespective of these discrepancies, endurance exercise training is effective in reducing oxidative damage of proteins in aged fast twitch muscle exposed to an oxidative challenge (Radak et al., 2002) and in reducing lipid oxidation in slow twitch muscle (Lambertucci et al., 2007).

On the basis of these observations, the purpose of this study was to determine if long-term treadmill endurance training initiated at late middle age (where muscle function has already begun to decline) and carried out into senescence (where functional declines become very severe), could attenuate the increase in oxidative damage (as reflected in carbonyls) through an increase in endogenous antioxidant enzyme activity. Secondly, we wanted to determine if these anticipated changes would attenuate the decline in contractile function in senescent skeletal muscle. Specifically, we hypothesized that treadmill endurance training would increase endogenous antioxidant activity, resulting in lower oxidative damage to the muscle. We further hypothesized that the decreased oxidative damage would translate to superior contractile function of the old trained animals versus old sedentary animals.