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The purpose of this study was to determine whether ultrastructural changes in intramyocellular lipid (IMCL) and mitochondria occur with aging. Muscle samples were analyzed from 24 young and 20 old, equally active, individuals for IMCL and mitochondria quantity and size as well as their association. Old men had larger IMCL droplets than all other groups in the total muscle area. Old individuals showed higher IMCL content in the subsarcolemmal area. Young participants had a greater number of mitochondria compared with old participants in both fiber regions and greater enzyme activities of cytochrome c oxidase and citrate synthase. The fraction of IMCL touching mitochondria was lowest in old women in the total area and in old men in the subsarcolemmal region. In summary, older adults have larger IMCL droplets, fewer mitochondria, and a lower proportion of IMCL in contact with mitochondria. These factors likely contribute to age-related reductions in mitochondrial function and lipid metabolism. Key Words: Mitochondrial dysfunction--Oxidative stress--Insulin resistance--Subsarcolemmal. doi: 10.1093/gerona/glp179

We investigated the effect of resistance exercise and feeding on the activation of signaling proteins involved in translation initiation. Nine young men (23.7 [+ or -] 0.41 yr; BMI = 25.5 [+ or -] 1.0 kg/[m.sup.2]; means [+ or -] SE) were tested twice after they performed a strenuous bout of unilateral resistance exercise, such that their contralateral leg acted as a nonexercised comparator, in either the fasted and fed [1,000 kJ, each 90 min (3 doses): 10 g protein, 41 g carbohydrate, 4 g fat] states. Muscle biopsies were obtained 6 h postexercise from both legs, resulting in four experimental conditions: rest-fasted, rest-fed, exercise-fasted, and exercise-fed. Feeding increased PKB/Akt (Ser473) phosphorylation (P < 0.05), while exercise increased the phosphorylation of Akt and the downstream 70 kDa $6 protein kinase ([p70.sup.S6K1], Thr389) and ribosomal protein $6 (rpS6, Ser235/236, Ser240/244; all P < 0.05). The combination of resistance exercise and feeding increased the phosphorylation of [p70.sup.S6Kl] (Thr389) and rpS6 (Ser240/244) above exercise alone (P < 0.05). Exercise also reduced phosphorylation of the catalytic epsilon subunit of eukaryotic initiation factor 2B (elF2B[epsilon], Ser540; P < 0.05). Mammalian target of rapamycin (mTOR, Ser2448), glycogen synthase kinase-3[beta] (GSK-3[beta], Ser9), and focal adhesion kinase (FAK, [Tyr.sup.576/577]) phosphorylation were unaffected by either feeding or resistance exercise (all P > 0.14). In summary, feeding resulted in phosphorylation of Akt, while resistance exercise stimulated phosphorylation of Akt, [p70.sup.S6K1], rpS6, and dephosphorylation elF2B[epsilon] with a synergistic effect of feeding and exercise on [p70.sup.S6K1] and its downstream target rpS6. We conclude that resistance exercise potentiates the effect of feeding on the phosphorylation and presumably activation of critical proteins involved in the regulation of muscle protein synthesis in young men. hypertrophy; lean body mass; protein accretion; weightlifting

Women use more fat during endurance exercise as evidenced by a lower respiratory exchange ratio (RER). The contribution of intramyocellular lipid (IMCL) to lipid oxidation during endurance exercise is controversial, and studies investigating sex differences in IMCL utilization have found conflicting results. We determined the effect of sex on net IMCL use during an endurance exercise bout using an ultrastructural evaluation. Men (n = 17) and women (n = 19) completed 90-min cycling at 63% [VO.sub.2peak]. Biopsies were taken before and after exercise and fixed for electron microscopy to determine IMCL size, # IMCL/area, IMCL area density, and the % IMCL touching mitochondria. Women had a lower RER and carbohydrate oxidation rate and a higher lipid oxidation rate during exercise (P < 0.05), compared with men. Women had a higher # IMCL/area and IMCL area density (P < 0.05), compared with men. Women, but not men, had a higher % IMCL touching mitochondria postexercise (P = 0.03). Exercise decreased IMCL area density (P = 0.01), due to a decrease in the # IMCL/area (P = 0.02). There was no sex difference in IMCL size or net use. In conclusion, women have higher IMCL area density compared with men, due to an increased # IMCL and not an increased IMCL size, as well as an increased % IMCL touching mitochondria postexercise. Endurance exercise resulted in a net decrease in IMCL density due to decreased number of IMCL, not decreased IMCL size, in both sexes. sex difference; electron microscopy; mitochondria; human

Methodological issues relevant to studies using microarrays and reverse transcription-polymerase chain reaction (RT-PCR) in human aging have rarely been evaluated. Because aging may accentuate biological differences between muscles, we compared transcriptome expression patterns, targeted messenger RNA (mRNA) abundance, strength, and muscle fiber type in the fight and left legs of older adults. Muscle biopsies were taken from each Vastus lateralis in eight older (71 [+ or -] 2 years) men, and isometric strength was determined. Samples were analyzed using an Affymetrix gene array, ATPase histochemistry, and RT-PCR for mRNA species involved in metabolism, apoptosis, vascular growth, and antioxidant status. Microarray analysis found that 31 of 5499 genes (0.6%) were significantly different between legs (negative log of the p value [NLOGP] [greater than or equal to] 2.0, but fold < 1.5), with only one gene, jumonji domain containing 1C (JMJD1C), being significantly different by [greater than or equal to] 1.50-fold. None of the mRNA species, or muscle fiber type, size, or strength, was different between legs. These findings are important for the design and analysis of studies using muscle data in older adults.

Impaired mitochondrial function and structure and intramyocellular lipid (IMCL) accumulation have been associated with obesity and Type 2 diabetes. We examined whether endurance exercise training and sex influenced IMCL and mitochondrial morphology using electron microscopy, whole-body substrate use, and mitochondrial enzyme activity. Untrained men (n = 5) and women (n = 7) were tested before and after 7 wk of endurance exercise training. Testing included 90 min of cycle ergometry at 60% [Vo.sub.2] peak with preexercise muscle biopsies analyzed for IMCL and mitochondrial size/area using electron microscopy and short-chain [beta]-hydroxyacyl-CoA dehydrogenase (SCHAD) and citrate synthase (CS) enzyme activity. Training increased the mean lipid area density (P = 0.090), the number of IMCL droplets (P = 0.055), the number of IMCL droplets in contact with mitochondria (P = 0.010), the total mitochondrial area (P < 0.001), and the size of individual mitochondrial fragments (P = 0.006). Women had higher mean lipid area density (P = 0.030) and number of IMCL droplets (P = 0.002) before and after training, but higher individual IMCL area only before training (P = 0.013), compared with men. Women oxidized more fat (P = 0.027) and less carbohydrate (P = 0.032) throughout the study. Training increased [Vo.sub.2 peak] (P < 0.001), %fat oxidation (P = 0.018), SCHAD activity (P = 0.003), and CS activity (P = 0.042). In summary, endurance exercise training increased IMCL area density due to an increase in the number of lipid droplets, whereas the increase in total mitochondrial area was due to an increase in the size of individual mitochondrial fragments. In addition, women have higher IMCL content compared with men due mainly to a greater number of individual droplets. Finally, endurance exercise training increased the proportion of IMCL in physical contact with mitochondria. intramuscular triglycerides; sex differences; lipid oxidation; mitochondria

Numerous studies from our and other laboratories have shown that women have a lower respiratory exchange ratio (RER) during exercise than equally trained men, indicating a greater reliance on fat oxidation. Differences in estrogen concentration between men and women likely play a role in this sex difference. Differing estrogen and progesterone concentrations during the follicular (FP) and luteal (LP) phases of the female menstrual cycle suggest that fuel use may also vary between phases. The purpose of the current study was to determine the effect of menstrual cycle phase and sex upon glucose turnover and muscle glycogen utilization during endurance exercise. Healthy, recreationally active young women (n = 13) and men (n = 11) underwent a primed constant infusion of [6,6-[sup.2]H]glucose with muscle biopsies taken before and after a 90-rain cycling bout at 65% peak [0.sub.2] consumption. LP women had lower glucose rate of appearance ([R.sub.a], P = 0.03), rate of disappearance ([R.sub.d], P = 0.03), and metabolic clearance rate (MCR, P = 0.04) at 90 rain of exercise and lower proglycogen (P = 0.04), macroglycogen (P = 0.04), and total glycogen (P = 0.02) utilization during exercise compared with FP women. Men had a higher RER (P = 0.02), glucose [R.sub.a] (P = 0.03), [R.sub.d] (P = 0.03), and MCR (P = 0.01) during exercise compared with FP women, and men had a higher RER at 75 and 90 min of exercise (P = 0.04), glucose [R.sub.a] (P = 0.01), [R.sub.d] (P = 0.01), and MCR (P = 0.001) and a greater PG utilization (P = 0.05) compared with LP women. We conclude that sex, and to a lesser extent menstrual cycle, influence glucose turnover and glycogen utilization during moderate-intensity endurance exercise. carbohydrate metabolism; menstrual phase; stable isotopes; humans; sex differences; exercise

The effect of aging on metabolic enzyme activity remains controversial, possibly due to physical activity differences. We examined the effect of aging on the enzyme activity for anaerobic and aerobic pathways in nonweight-bearing human skeletal muscle from relatively sedentary males. The muscle obliquus internus abdominis was analyzed for anaerobic (creatine kinase, adenylate kinase, and lactate dehydrogenase) and aerobic (2-oxoglutarate dehydrogenase and carnitine palmitoyltransferase) enzyme activities in two groups: middle-aged (29-54 years) and older (61-74 years) adults. All enzyme activities were lower in older versus middle-aged adults when results were expressed as muscle wet weight (p < .05). When activity was expressed relative to the protein content, only lactate dehydrogenase remained significantly lower in older versus middle-aged adults (p < .001). In conclusion, some of the reduction in muscle performance in older adults may be due to lower activity of the anaerobic and aerobic enzymes as well as protein content, not solely due to a decrease in physical activity.

Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the decline in muscle mass-specific skeletal muscle aerobic function is unknown. We used a pump-perfused rat hind-limb model to examine maximal aerobic performance (V[O.sub.2max]) in young adult (YA; 8-9-month-old), late middle aged (LMA; 28-30-month-old) and senescent (SEN; 36-month-old) Fischer 344 x Brown Norway F1-hybrid rats at matched rates of convective [O.sub.2] delivery (Q[O.sub.2]). Despite similar muscle Q[O.sub.2] during a 4-minute contraction bout, muscle mass-specific V[O.sub.2max] was reduced in LMA (15%) and SEN (52%) versus YA. In plantaris muscle homogenates, nested polymerase chain reaction revealed an increased frequency of mitochondrial DNA deletions in the older animals. A greater reduction in the flux through electron transport chain complexes I-III than citrate synthase activity in the older animals suggests mitochondrial dysfunction consequent to mitochondrial DNA damage with aging. These results support the hypothesis that a reduced oxidative capacity, due in part to age-related mitochondrial dysfunction, contributes to the decline in aerobic performance in aging skeletal muscles.

Two receptors activated by the corticotropin-releasing factor (CRF) family of peptides have been identified, the CRF 1 receptor (CRFIR) and the CRF 2 receptor (CRF2R). Of these, the CRF2R is expressed in skeletal muscle. To understand the role of the CRF2R in skeletal muscle, we utilized CRFR knockout mice and CRF2R-selective agonists to modulate nerve damage and corticosteroid- and disuse-induced skeletal muscle atrophy in mice. These analyses demonstrated that activation of the CRF2R decreased nerve damage and corticosteroid- and disuse-induced skeletal muscle mass and function loss. In addition, selective activation of the CRF2R increased nonatrophy skeletal muscle mass. Thus we describe for the first time a novel activity of the CRF2R, modulation of skeletal muscle mass. atrophy; hypertrophy; corticotropin-releasing factor receptor; sauvagine; urocortin II

We sought to determine whether creatine monohydrate (CrM) supplementation would enhance the increases in strength and fat-free mass that develop during resistance exercise training in older adults. Twenty-eight healthy men and women over the age of 65 years participated in a whole-body resistance exercise program 3 days per week for 14 weeks. The study participants were randomly allocated, in a double-blind fashion, to receive either CrM (5 g/d + 2 g of dextrose; n = 14) or placebo (7 g of dextrose; n = 14). The primary outcome measurements included the following: total body mass, fat-free mass, one-repetition maximum strength for each body part, isometric knee extension, handgrip, and dorsiflexion strength, chair stand performance, 30-m walk test, 14-stair climb performance, muscle fiber type and area, and intramuscular total creatine. Fourteen weeks of resistance exercise training resulted in significant increases in all measurements of strength and functional tasks and muscle fiber area for both groups (p < .05). CrM supplementation resulted in significantly greater increases in fat-free mass and total body mass, as compared with placebo (p < .05). The CrM group also showed a greater increase in isometric knee extension strength in men and women, as compared with placebo (p < .05), and also greater gains in isometric dorsiflexion strength (p < .05), but in men only. There was a significant increase in intramuscular total creatine in the CrM group (p < .05). Finally, there were no significant side effects of treatment or exercise training. This study confirms that supervised heavy resistance exercise training can safely increase muscle strength and functional capacity in older adults. The addition of CrM supplementation to the exercise stimulus enhanced the increase in total and fat-free mass, and gains in several indices of isometric muscle strength.

However, our patient was young, with normal renal function before the rhabdomyolysis, and at this degree of CK elevation, an average 30-day risk of kidney injury is 74%, with only 11% of patients requiring renal replacement therapy.[15] In addition, our patient also had markedly elevated liver enzymes. Conclusion We report a case of rhabdomyolysis, possibly associated with mRNA vaccination against SARS-CoV-2, in a patient with I RYR1 i mutation whose other risk factors included use of a statin and multiple antipsychotic medications. We report a case of severe rhabdomyolysis in a patient with a ryanodine receptor 1 ( I RYR1 i ) gene mutation who presented 8 days after receiving a second dose of Moderna mRNA vaccine against SARS-CoV-2. In these patients, we suggest clinicians obtain serum CK levels within 7 days of vaccination and advise patients to monitor for clinical features of rhabdomyolysis. [Extracted from the article]