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Skeletal muscle, one of the largest organs in the human body, undergoes major biological, phenotypic, and functional changes during the aging process. The whole muscle mass declines with aging with a faster rate than the overall fat‐free mass. The decline starts already around the fourth decade of life and accelerates after the age of 70 [1]. The parallel decline of strength exceeds the rate expected from the decline in mass, and this is consistent with profound biological and architectural changes observed in muscles during the aging process both in animal models and in humans [2].

The primary function of muscles is to generate mechanical force, which is essential for the movement of different body parts while accomplishing fundamental functions such as walking, manufacturing and handling objects, moving the eyes, expanding and compressing the lungs, controlling the opening and closing of larynx among many others. Production of mechanical force requires energy that is provided by the hydrolysis of a high‐energy transfer phosphate bond in adenosine 5′‐triphosphate (ATP) to produce adenosine diphosphate (ADP) and inorganic phosphate. The flow of energy continuously matches the energy demand through the phosphocreatine (PCr) shuttle, a system that facilitates transfer of high‐energy phosphate from muscle cell mitochondria to myofibrils (Figure 3.1). Interestingly, more than 95% of creatine in the body is located in striate muscle, where the fluctuation of energy utilization is the highest [3]. Beyond contraction, skeletal muscle health also requires a constant flux of energy to maintain the activity of the sodium/potassium pumps and ensure calcium transport and sequestration in compartments. The energy for these activities is a substantial portion of the total energy consumption in resting muscle, but accounts only for a small percentage of energy utilization during intense contraction [4].

Figure 3.1 Phosphocreatine (PCr) shuttle: the ATP generated by the complex V of the electron transport chain converts creatine into PCr in mitochondrial matrix, which in turn allows ADP phosphorylation in the sarcoplasm. The ATP generated will fuel the muscle contraction through interaction with the myosin chains of the sarcomere, the maintenance of membrane, and calcium (Ca²⁺) sequestration in the sarcoplasmic reticulum. ADP = adenosine diphosphate; ATP = adenosine 5′‐triphosphate; CK = creatine kinase; K⁺ = potassium; Na⁺ = sodium.

The concentration of ATP in human quadriceps muscles is ~5.5 mM (expressed per 1 kg of whole muscle tissue) [5] and during contraction the rate of ATP hydrolysis increases to ~18 mM/min (moderate intensity) to 55–80 mM/min for submaximal isometric contraction, and as high as 160 mM/min for a dynamic contraction generating maximal power. Thus, in the absence of a fresh supply, the ATP already present could only support 5.5/80 = 0.0685 minute or ~4 seconds of contraction. Hence, efficient and intense production of force in skeletal muscle requires continuous ATP regeneration, which occurs through the hydrolysis of PCr. During a brief exercise the decline of PCr and increase of inorganic phosphorous are the only evident biochemical changes in muscle tissue [6]. Of note, even though PCr functions as an accumulator of chemical energy, its concentration is only fourfold greater than that of ATP and, therefore, could only support contraction for a few more seconds if not continuously recharged by ATP produced by mitochondria. At low levels of exercise, the system can stay stable for prolonged time, but when the exercise becomes intense it overcomes the capacity of energy generation, both aerobically and anaerobically [6]. This is the reason why intense and repeated contractions can be sustained only for a short time, and as the rate of energy production slows down with aging, the time prior to fatigue becomes progressively shorter. Of note, when the contraction ceases, the ATP generated by mitochondria fully recharges PCr that rises back to its pre‐exercise concentration. The rate of PCr recovery is assessed by ³¹phosphorous magnetic resonance spectroscopy to estimate maximal mitochondrial function [7].

Given the critical role of energy availability for the proper functionality of skeletal muscle, it is not surprising that mitochondrial dysfunction has been hypothesized to be the primary cause of age‐related sarcopenia [8]. This hypothesis is consistent with the fact that several maternally inherited mutations in mitochondrial DNA (mtDNA) genes and some mutations that affect nuclear genes that code for mitochondrial proteins are associated with impaired energetic metabolism and cause different degrees of myopathy with some similarities with age‐associated sarcopenia and often associated with brain impairments [9]. In addition, a gene expression study recently performed in a multiethnic population strongly suggested that a decline in mitochondrial integrity and mass is the biological hallmark of frailty and age‐related sarcopenia [10].