Sarcopenia. Группа авторов

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].

EVIDENCE THAT MITOCHONDRIAL FUNCTION DECLINES WITH AGING AND ITS CONSEQUENCES ON MUSCLE HEALTH AND FUNCTION

      Several lines of research suggest that skeletal muscle mitochondrial volume and function decline with aging even in healthy individuals, and that the magnitude of this decline is larger in individuals with severe multimorbidity and those who are sedentary [8, 11]. Moreover, chronic exercise robustly increases mitochondrial capacity within muscles in older adults [12, 13], and exercise appears to more strongly correlate with mitochondrial content and performance than aging [14, 15]. However, the causal role of mitochondrial dysfunction in the genesis of sarcopenia has not been definitively established, with conflicting results across studies, remaining an area of intense investigation.

Animal studies have shown a decline in mitochondrial mass and number in skeletal muscle with aging, findings that have been confirmed in aging humans [16–21]. Most although not all studies conducted on muscle tissue using both confocal microscopy and electron microscopy have demonstrated that the number and shape of mitochondria, as well as the overall mitochondrial mass, decline with aging [22]. This is consistent with the discovery studies showing that mitochondrial transcripts and proteins are the most underrepresented classes of transcripts and proteins with older age in skeletal muscle [23]. Of note, proteomic studies indicate that the entire class of mitochondrial proteins becomes underrepresented with aging even in very healthy individuals, including structural proteins, proteins that are part of the electron transport chain (ETC) complexes, as well as critical enzymes for glycolysis and Krebs cycle (Figure 3.2) [24]. This is consistent with the idea that the whole mitochondrial mass declines with aging as percentage of muscle mass (or more precisely percentage of muscle proteins).

      The decline of mitochondrial mass and function have important consequences for muscle health. Studies conducted with ³¹P MRI spectroscopy have shown that maximal ATP production (or maximal oxidative capacity) declines with aging even in relatively healthy individuals [25]. The decline of mitochondrial oxidative capacity with aging has been also confirmed “ex vivo;” by conducting respirometry on permeabilized muscle fibers from human biopsies [23, 26]. Such decline accounts for a significant percentage of the decline of muscle strength and walking speed observed with aging [27], is associated with fatigability [28] and sarcopenia [29, 30], and is a strong correlate of cardiorespiratory fitness [23, 26] and the development of insulin resistance [31].