Payne, Anthony M., Stephen L. Dodd, and Christiaan Leeuwenburgh. Life-long calorie restriction in Fischer 344 rats attenuates age-related loss in skeletal musclespecific force and reduces extracellular space. The decline in muscle function is associated with an age-related decrease in muscle mass and an age-related decline in strength. However, decreased strength is not solely due to decreased muscle mass. The age-related decline in muscle-specific force (force/muscle cross-sectional area), a

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... asure of intrinsic muscle function, also contributes to age-related strength decline, and the mechanisms by which this occurs are only partially known. Moreover, changes in the extracellular space could have a profound effect on skeletal muscle function. Life-long calorie restriction in rodents has shown to be a powerful anti-aging intervention. In this study, we examine whether calorie restriction is able to attenuate the loss of muscle function and elevations in extracellular space associated with aging. We hypothesize that calorie restriction attenuates the age-associated decline in specific force and increases in extracellular space. Measurements of in vitro contractile properties of the extensor digitorum longus (type II) and soleus (type I) muscles from 12-mo and 26-to 28-mo-old ad libitum-fed, as well as 27-to 28-mo-old life-long calorie-restricted male Fischer 344 rats, were performed. We found that calorie restriction attenuated the age-associated decline in muscle mass-to-body mass ratio (mg/g) and strength-to-body mass ratio (N/kg) in the extensor digitorum longus muscle (P Ͻ 0.05) but not in the soleus muscle (P Ͼ 0.05). Importantly, muscle-specific force (N/cm 2 ) in the extensor digitorum longus, but not in the soleus muscle, of the old calorie-restricted rats was equal to that of the young 12-mo-old animals. Moreover, the age-associated increase in extracellular space was reduced in the fast-twitch extensor digitorum longus muscle (P Ͻ 0.05) but not in the soleus muscle with calorie restriction. We also found a significant correlation between the extracellular space and the muscle-specific force in the extensor digitorum longus (r ϭ Ϫ0.58; P Ͻ 0.05) but not in the soleus muscle (r ϭ Ϫ0.38; P Ͼ 0.05). Hence, this study shows a loss of muscle function with age and suggests that long-term calorie restriction is an effective intervention against the loss of muscle function with age. fiber specific; glycoxidative stress; aging; deletions; mitochondria; calorie restriction THE DECREASE IN MUSCLE STRENGTH with age presents a significant health problem estimated to cost society billions of dollars over the next few decades (15, 36, 37). By the year 2030, the elderly population will grow from 13 to ϳ20% of the total population, and it is estimated that $130 billion will be imposed by physical frailty (15, 36, 37) . Age-related loss of strength contributes to disability and frailty in the elderly, leading to the inability to perform daily living tasks (2, 3, 5). The well-recognized age-related decrease in muscle mass contributes to the age-related decline in strength (16, 19, 28, 30, 39) . Muscle mass declines at a greater rate with age than body mass (51) and fat-free mass (22, 55), reducing strength-to-weight ratio and possibly leading to disability and loss of independence (50, 53, 58). Decreased strength is not, however, solely due to decreased muscle mass. The age-related decline in muscle-specific force [force/muscle cross-sectional area (CSA)], a measure of intrinsic muscle function, also contributes to age-related strength decline (17, 28, 30, 32, 51, 52) . Evidence of this phenomenon has been found in vivo in humans by measuring isokinetic-specific (19, 28, 30) and isometric-specific (31, 56) force. Magnetic resonance imaging (18, 19) and computed tomography (38, 46) have revealed increased nonmuscle tissue within quadriceps (19, 38), hamstrings (38), plantar flexors (18, 46), and spinalis (18) muscle groups with age. These changes would contribute to a decrease in specific force. In vitro investigations of rodent muscle have also shown decreased muscle-specific force with age (17, 29, 32) . Mechanisms attributed to these findings include decreases in actin-myosin cross-bridge stability (29) and impairments in excitation-contraction coupling (9, 45), but many other potential mechanisms still require further investigation. Hence, understanding all mechanisms of sarcopenia could potentially permit the development of strategies and interventions that may attenuate the loss of skeletal muscle myocytes and sarcopenia associated with Original submission in response to a call for papers on "Physiology of Aging." Address for reprint requests and other correspondence: C. Leeuwenburgh, Biochemistry of Aging Laboratory, or S. Dodd, Muscle