Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.

The effects of strength conditioning on skeletal muscle function and mass were determined in older men. Twelve healthy untrained volunteers (age range 60-72 yr) participated in a 12-wk strength training program (8 repetitions/set; 3 sets/day; 3 days/wk) at 80% of the one repetition maximum (1 RM) for extensors and flexors of both knee joints. They were evaluated before the program and after 6 and 12 wk of training. Weekly measurements of 1 RM showed a progressive increase in strength in extensors and flexors. By 12 wk extensor and flexor strength had increased 107.4 (P less than 0.0001) and 226.7% (P less than 0.0001), respectively. Isokinetic peak torque of extensors and flexors measured on a Cybex II dynamometer increased 10.0 and 18.5% (P less than 0.05) at 60 degrees/s and 16.7 and 14.7% (P less than 0.05) at 240 degrees/s. The torque-velocity relationship showed an upward displacement of the curve at the end of training, mainly in the slow-velocity high-torque region. Midthigh composition from computerized tomographic scans showed an increase (P less than 0.01) in total thigh area (4.8%), total muscle area (11.4%), and quadriceps area (9.3%). Biopsies of the vastus lateralis muscle revealed similar increases (P less than 0.001) in type I fiber area (33.5%) and type II fiber area (27.6%). Daily excretion of urinary 3-methyl-L-histidine increased with training (P less than 0.05) by an average 40.8%. Strength gains in older men were associated with significant muscle hypertrophy and an increase in myofibrillar protein turnover.

The present study examines age-related changes in skeletal muscle size and function after 12 yr. Twelve healthy sedentary men were studied in 1985-86 (T1) and nine (initial mean age 65.4 +/- 4.2 yr) were reevaluated in 1997-98 (T2). Isokinetic muscle strength of the knee and elbow extensors and flexors showed losses (P < 0.05) ranging from 20 to 30% at slow and fast angular velocities. Computerized tomography (n = 7) showed reductions (P < 0.05) in the cross-sectional area (CSA) of the thigh (12.5%), all thigh muscles (14.7%), quadriceps femoris muscle (16.1%), and flexor muscles (14. 9%). Analysis of covariance showed that strength at T1 and changes in CSA were independent predictors of strength at T2. Muscle biopsies taken from vastus lateralis muscles (n = 6) showed a reduction in percentage of type I fibers (T1 = 60% vs. T2 = 42%) with no change in mean area in either fiber type. The capillary-to-fiber ratio was significantly lower at T2 (1.39 vs. 1. 08; P = 0.043). Our observations suggest that a quantitative loss in muscle CSA is a major contributor to the decrease in muscle strength seen with advancing age and, together with muscle strength at T1, accounts for 90% of the variability in strength at T2.

Skeletal muscle is one of the most dynamic and plastic tissues of the human body. In humans, skeletal muscle comprises approximately 40% of total body weight and contains 50-75% of all body proteins. In general, muscle mass depends on the balance between protein synthesis and degradation and both processes are sensitive to factors such as nutritional status, hormonal balance, physical activity/exercise, and injury or disease, among others. In this review, we discuss the various domains of muscle structure and function including its cytoskeletal architecture, excitation-contraction coupling, energy metabolism, and force and power generation. We will limit the discussion to human skeletal muscle and emphasize recent scientific literature on single muscle fibers.

Smoothness is characteristic of coordinated human movements, and stroke patients' movements seem to grow more smooth with recovery. We used a robotic therapy device to analyze five different measures of movement smoothness in the hemiparetic arm of 31 patients recovering from stroke. Four of the five metrics showed general increases in smoothness for the entire patient population. However, according to the fifth metric, the movements of patients with recent stroke grew less smooth over the course of therapy. This pattern was reproduced in a computer simulation of recovery based on submovement blending, suggesting that progressive blending of submovements underlies stroke recovery.

The isokinetic strength of the elbow and knee extensors and flexors was measured in 200 healthy 45- to 78-yr-old men and women to examine the relationship between muscle strength, age, and body composition. Peak torque was measured at 60 and 240 degrees/s in the knee and at 60 and 180 degrees/s in the elbow by use of a Cybex II isokinetic dynamometer. Fat-free mass (FFM) was estimated by hydrostatic weighing in all subjects, and muscle mass (MM) was determined in 141 subjects from urinary creatinine excretion. FFM and MM were significantly lower (P less than 0.001) in the oldest group. Strength of all muscle groups at both testing speeds was significantly (P less than 0.006) lower (range 15.5-26.7%) in the 65- to 78- than in the 45- to 54-yr-old men and women. When strength was adjusted for FFM or MM, the age-related differences were not significant in all muscle groups except the knee extensors tested at 240 degrees/s. Absolute strength of the women ranged from 42.2 to 62.8% that of men. When strength was expressed per kilogram of MM, these gender differences were smaller and/or not present. These data suggest that MM is a major determinant of the age- and gender-related differences in skeletal muscle strength. Furthermore, this finding is, to a large extent, independent of muscle location (upper vs. lower extremities) and function (extension vs. flexion).

The longitudinal changes in isokinetic strength of knee and elbow extensors and flexors, muscle mass, physical activity, and health were examined in 120 subjects initially 46 to 78 years old. Sixty-eight women and 52 men were reexamined after 9.7 +/- 1.1 years. The rates of decline in isokinetic strength averaged 14% per decade for knee extensors and 16% per decade for knee flexors in men and women. Women demonstrated slower rates of decline in elbow extensors and flexors (2% per decade) than men (12% per decade). Older subjects demonstrated a greater rate of decline in strength. In men, longitudinal rates of decline of leg muscle strength were approximately 60% greater than estimates from a cross-sectional analysis in the same population. The change in leg strength was directly related to the change in muscle mass in both men and women, and it was inversely related to the change in medication use in men. Physical activity declined yet was not directly associated with strength changes. Although muscle mass changes influenced the magnitude of the strength changes over time, strength declines in spite of muscle mass maintenance or even gain emphasize the need to explore the contribution of other cellular, neural, or metabolic mediators of strength changes.

On average, FM increased; however, the increase in women was attenuated with advancing age. The decrease in FFM over the follow-up period was small and masked the wide interindividual variation that was dependent on the magnitude of weight change. The contribution of weight stability, modest weight gains, or lifestyle changes that include regular resistance exercise in attenuating lean-tissue loss with age should be explored.