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Skeletal muscle atrophy has extreme adverse consequences. Molecular mechanisms that mediate the process of atrophy are not well defined. Recent studies have focused on diverse molecular cascades that control the activation of ubiquitin ligases, indicating that the involvement of the ubiquitin proteasome may be common to a range of atrophic stimuli.
STUDY DESIGN: This study was conducted by retrospective case selection and prospective observation of longitudinal changes of the multifidus muscle cross-sectional area and of trunk extension muscle strength in percutaneous and open pedicle screw fixations. OBJECTIVES: To compare postoperative multifidus muscle atrophy and trunk muscle performance of percutaneous pedicle screw fixation against those of open pedicle screw fixation. SUMMARY OF BACKGROUND DATA: Recent attempts to combine percutaneous pedicle screw fixation with minimally invasive fusion techniques are based on an anecdotal presupposition that percutaneous pedicle screw fixation is superior to its open counterpart. However, the benefits of percutaneous pedicle screw fixation are currently poorly defined. METHODS: Nineteen enrolled patients were divided as follows: 11 in the open pedicle screw fixation group (OPF group) and eight in the percutaneous pedicle screw fixation group (PPF group). The preoperative and postoperative cross-sectional area and T2-weighted signal intensity of multifidus muscle were measured by MRI, and trunk extension muscle strength was measured. In addition, various clinical variables were compared between two groups. RESULTS: There was significant decrease in the cross-sectional area of multifidus muscle in the OPF group. In contrast, the results in the PPF group showed no statistical difference between preoperative results and that of the follow-up MRI. Although percutaneous pedicle screw fixation had positive effects on postoperative trunk muscle performance, clinical outcomes were not significantly different in areas of pain score, JOA score, and patient's opinion regarding the outcome of the surgery. However, percutaneous pedicle screw fixation caused less blood loss, and the proportion of patients who did not need postoperative oral analgesics was greater in the PPF group. CONCLUSIONS: Percutaneous pedicle screw fixation caused less paraspinal muscle damage than open pediclescrew fixation and had positive effects on postoperative trunk muscle performance.
Skeletal muscle size is modulated by a number of factors, including muscle load, utilization, and regenerative capacity. Surprisingly, actions that can promote muscle growth do not necessarily prevent the loss of muscle mass, or atrophy. This suggests that divergent mechanisms are important for the maintenance of muscle mass in different contexts. In acute atrophy, muscles rapidly lose mass when load is lacking, and this response seems to involve active elimination of myonuclei. In contrast, chronic atrophy, such as loss of muscle mass related to aging, is associated with impairments in muscle repair. In this review, two contexts in which muscle mass is lost are explored to determine if similar processes are involved.
In adults, the volume of quadriceps femoris muscle decreases with age, whereas the impact of increasing age on the size of other extremity muscles was hardly studied. This study was conducted to examine whether age-related muscle atrophy is a general phenomenon, whether it is accompanied by increasing subcutaneous fat and whether physical activity can compensate age-related muscle atrophy. One hundred and two female and 101 male subjects (aged 19-86 years), with common physical activity, as well as 29 women and 38 men (aged 20-81 years) regularly performing sports at least 3 h per week for several years (mean, 10 years in women and 14 years in men, respectively), were examined. Both in athletes and control subjects, the thickness of thigh muscles significantly decreased with age (-15(-)-21% from age 20 to age 70), whereas diameter of upper arm muscles remained nearly unchanged. Diameters of the calf muscle decreased with advancing age only in the control group. In male control subjects, the tibialis anterior muscle shrunk as well. Except for the vastus lateralis muscle in women, the relative loss of muscle thickness was more evident in control subjects than in athletes. Thickness of the subcutaneous fat layers remained almost unchanged. In summary, not all extremity muscles exhibit age-related decrease in size. Regular physical activity can ease off muscle atrophy.
Muscle atrophy and wasting is a serious problem that occurs in patients with prolonged debilitating illness, burn injury, spinal injury, as well as with space flight. Current treatment for such atrophy, which often relies on nutritional supplementation and physical therapy, is of limited value in preventing the muscle wasting that occurs. Considerable recent attention has focused on the use of anabolic growth factors such as insulin-like growth factor (IGF-1) in preventing muscle atrophy during limb disuse or with various catabolic conditions. However, potential side effects such as hypoglycemia appear to be limiting factors in the usefulness of IGF-1 for clinical treatment of muscle wasting conditions. The formulation of IGF-1 used in this study (IGF-1/BP3) is already bound to its endogenous-binding protein (BP3) and, as a result, has a greater specificity of action and significantly less hypoglycemic effect. Using a rat model of hind limb suspension (HLS) for 10 days, we induced marked muscle atrophy that was accompanied by enhanced muscle proteolysis and reduced muscle protein content. When HLS rats were treated with IGF-1/BP3 (50 mg/kg, b.i.d.), they retained greater body and muscle mass. Muscle protein degradation was significantly reduced and muscle protein content was preserved. The rate of protein synthesis, although somewhat reduced in HLS muscle, was not significantly elevated by IGF-1/BP3 treatment. Volume density of HLS-treated muscles were increased compared to untreated HLS rats and the actual number of fibers per area of muscle was likewise increased. The results of the current study suggest that IGF-1/BP3 might be useful for inhibiting muscle proteolysis in catabolic conditions and thus preserving muscle protein content and mass.
PURPOSE: To evaluate associated findings in patients who exhibited atrophy of infraspinatus muscle at magnetic resonance (MR) examination of their shoulders to clarify implications of this abnormality. MATERIALS AND METHODS: With an electronic database search, cases of advanced infraspinatus muscle atrophy in patients who underwent MR imaging during a 1-year period for evaluation of shoulder pain or dysfunction were identified. The analysis was restricted to cases interpreted by one reader who applied a standardized method of reporting. Associated MR imaging findings in these cases were tabulated. RESULTS: Advanced infraspinatus muscle atrophy was encountered in 51 (4.3%) of 1,191 MR examinations of the shoulder. Tears of the infraspinatus tendon were present in only 27 (53%) of 51 cases. In 46 (90%) of 51 cases, a full-thickness tear was present in the anterior portion of the rotator cuff. In 10 (20%) of 51 cases with infraspinatus muscle atrophy, cuff muscle atrophy was confined to the infraspinatus muscle. Cuff muscle atrophy was isolated to the infraspinatus muscle in four (17%) of 24 cases in which atrophy of the infraspinatus muscle was present despite an intact tendon. In none of the 51 cases was there a mass in the suprascapular or sphenoglenoid notch. CONCLUSION: Infraspinatus muscle atrophy typically occurs with tendon tears in the anterior aspect of the rotator cuff. Concomitant atrophy in the supraspinatus muscle often is present, but infraspinatus muscle atrophy can occur in isolation, and this finding does not imply that the infraspinatus tendon is ruptured.
Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.
BACKGROUND: While total knee arthroplasty reduces pain and provides a functional range of motion of the knee, quadriceps weakness and reduced functional capacity typically are still present one year after surgery. The purpose of the present investigation was to determine the role of failure of voluntary muscle activation and muscle atrophy in the early loss of quadriceps strength after surgery. METHODS: Twenty patients with unilateral knee osteoarthritis were tested an average of ten days before and twenty-seven days after primary total knee arthroplasty. Quadriceps strength and voluntary muscle activation were measured with use of a burst-superimposition technique in which a supramaximal burst of electrical stimulation is superimposed on a maximum voluntary isometric contraction. Maximal quadriceps cross-sectional area was assessed with use of magnetic resonance imaging. RESULTS: Postoperatively, quadriceps strength was decreased by 62%, voluntary activation was decreased by 17%, and maximal cross-sectional area was decreased by 10% in comparison with the preoperative values; these differences were significant (p < 0.01). Collectively, failure of voluntary muscle activation and atrophy explained 85% of the loss of quadriceps strength (p < 0.001). Multiple linear regression analysis revealed that failure of voluntary activation contributed nearly twice as much as atrophy did to the loss of quadriceps strength. The severity of knee pain with muscle contraction did not change significantly compared with the preoperative level (p = 0.31). Changes in knee pain during strength-testing did not account for a significant amount of the change in voluntary activation (p = 0.14). CONCLUSIONS: Patients who are managed with total knee arthroplasty have profound impairment of quadriceps strength one month after surgery. This impairment is predominantly due to failure of voluntary muscle activation, and it is also influenced, to a lesser degree, by muscle atrophy. Knee pain with muscle contraction played a surprisingly small role in the reduction of muscle activation.
The morphologic changes in denervation atrophy of paravertebral muscles after severance of the posterior rami in cats were investigated, using histochemical methods and electromyography. Using a paraspinal approach, three branches of the posterior rami on the left side were cut under microscopy at one, two, or three levels (L2 approximately L4). Muscle atrophy was evaluated, using the percent wet weight and the percent diameter of muscle fibers as parameters. Myosine ATPase stain was used to observe reinnervation. Four weeks after surgery, the range and severity of muscle atrophy increased proportionally to the number of posterior rami severed. Muscle atrophy was revealed at one or two levels caudal to the injured nerve level. At 12 and 24 weeks, muscle atrophy recovered gradually. In more than two-level injury groups, however, recovery of percent wet weight reached up to 80% even after 24 weeks, despite the fact of reinnervation demonstrated in some parts of the denervated muscles.
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BACKGROUND: The purpose of this study was to investigate the prevalence of skeletal muscle atrophy and its relation to exercise intolerance and abnormal muscle metabolism in patients with heart failure (HF). METHODS AND RESULTS: Peak VO2, percent ideal body weight (% IBW), 24-hour urine creatinine (Cr), and anthropometrics were measured in 62 ambulatory patients with HF. 31P magnetic resonance spectroscopy (MRS) and imaging (MRI) of the calf were performed in 15 patients with HF and 10 control subjects. Inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were measured at rest and during exercise. Calf muscle volume was determined from the sum of the integrated area of muscle in 1-cm-thick contiguous axial images from the patella to the calcaneus. A reduced skeletal muscle mass was noted in 68% of patients, as evidenced by a decrease in Cr-to-height ratio of less than 7.4 mg/cm and/or upper arm circumference of less than 5% of normal. Calf muscle volume (MRI) was also reduced in the patients with HF (controls, 675 +/- 84 cm3/m2; HF, 567 +/- 112 cm3/m2; p less than 0.05). Fat stores were largely preserved with triceps skinfold of less than 5% of normal and/or IBW of less than 80% in only 8% of patients. Modest linear correlations were observed between peak VO2 and both calf muscle volume per meter squared (r = 0.48) and midarm muscle area (r = 0.36) (both p less than 0.05). 31P metabolic abnormalities during exercise were observed in the patients with HF, which is consistent with intrinsic oxidative abnormalities. The metabolic changes were weakly correlated with muscle volume (r = -0.42, p less than 0.05). CONCLUSIONS: These findings indicate that patients with chronic HF frequently develop significant skeletal muscle atrophy and metabolic abnormalities. Atrophy contributes modestly to both the reduced exercise capacity and altered muscle metabolism.
Human disuse muscle atrophy frequently accompanies orthopedic injury, arthritis, or bed rest, and recovery is often incomplete despite current rehabilitation programs. We have studied the vastus lateralis muscle in 12 patients with chronic disuse atrophy associated with chronic osteoarthritis of the hip both preoperatively and after total hip arthroplasty. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated an increase in the level of expression of myostatin, insulin-like growth factor-1 (IGF-1) and leukemia inhibitory factor (LIF) mRNAs compared to healthy control muscle. In all patients there was a significant correlation preoperatively between increasing myostatin mRNA expression and reduction in type 2A and 2B fiber area. In the 8 female patients there was a significant correlation between increased myostatin mRNA expression and the atrophy factor calculated for 2A and 2B fiber types preoperatively. We hypothesize that a complex interaction occurs between muscle growth regulating factors in the genesis of muscle wasting. Our results indicate that myostatin is a muscle-wasting factor contributing to type 2B and 2A atrophy. Other muscle growth factors, such as IGF-1 and LIF, may be upregulated in a counterregulatory fashion or may be involved in the fiber type switching seen in disuse muscle wasting.
Exercise has been shown to be effective in preventing glucocorticoid-induced atrophy in muscles containing high proportions of type II or fast-twitch fibers. This investigation was undertaken to further evaluate this response in type IIa and IIb fibers, determined by histochemical staining for myofibrillar adenosinetriphosphatase with alkaline and acid preincubation. Steroid [cortisol acetate (CA), 100 mg/kg body wt] and exercise (running 90 min/day, 29 m/min) treatments were initiated simultaneously for 11 consecutive days in female rats. Fiber distribution and area measurements were performed in a deep and superficial region of plantaris muscle. The exercise regimen spared approximately 40% of the CA-induced plantaris muscle atrophy. In the deep region, the fiber population, which contained approximately 13% type I (slow-twitch), 24% type IIa, and 63% IIb fibers, was not affected by either treatment. In the superficial section, which consisted solely of type II fibers, the proportion of type IIa fibers was higher (27 vs. 9%, P less than 0.01) in the steroid- than in the vehicle-treated groups. Within each region, type IIa fibers were less susceptible to atrophy than type IIb fibers, and within each fiber type, the deep region had less atrophy than the superficial region. Type I fibers were unchanged by steroid treatment. For type IIa fibers, exercise prevented 100% of the atrophy in the deep region and 50% in the superficial region. For type IIb fibers, the activity spared 67 and 40% of the atrophy in these same regions, respectively. These results show that glucocorticoids are capable of changing the myosin phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Skeletal muscle atrophy is a common comorbidity of cancer. The cellular signaling mechanisms that regulate muscle size constitute a balance of the protein breakdown pathways upregulated during atrophy, and the protein synthesis pathways that are activated during skeletal muscle hypertrophy. In this issue of Cancer Cell, Acharyya et al. demonstrate a new and surprising regulatory axis that is centered around dystrophin, the protein that is mutated in settings of muscular dystrophy. These data reposition dystrophin as a signaling protein and connect an important cellular complex required for the structural integrity of muscle to the pathways that modulate muscle size.
PURPOSE OF REVIEW: Many situations cause muscle atrophy. When severe, muscle atrophy is associated with an increase in morbidity and mortality. This loss of muscle mass is thought to be due to an imbalance between catabolic and anabolic pathways, resulting in an increase of muscle protein proteolysis and in a decrease in protein synthesis. Changes in muscle levels of muscle growth factors are thought to play a major role in this imbalance. Despite recent better understanding of the metabolic and molecular derangements leading to muscle wasting, therapy of muscle atrophy still has a poor success rate. RECENT FINDINGS: The recent demonstration that changes in local growth factors, such as insulin-like growth factor-I and myostatin, occur during muscle atrophy has stimulated research interest to prevent muscle mass loss by delivering these growth factors or their inhibitors into the muscle. During the last few years, several advances in the field of muscle gene transfer, using electroporation or recombinant adeno-associated viral vectors, have opened novel therapeutic ways to deliver growth factors able to counteract the loss of muscle mass. SUMMARY: Preventing decrease of insulin-like growth factor-I muscle, or inhibiting myostatin action by local genes over-expression, may provide a clinically relevant avenue for the preservation, attenuation or reversal of disease-related muscle loss.
Atrophy of skeletal muscle leads to decreases in myofiber size and nuclear number; however, the effects of atrophic conditions on muscle precursor cells (MPC) are largely unknown. MPC lie outside myofibers and represent the main source of additional myonuclei necessary for muscle growth and repair. In the present study, we examined the properties of MPC after hindlimb suspension (HS)-induced atrophy and subsequent recovery of the mouse hindlimb muscles. We demonstrated that the number of MPC in atrophied muscles was decreased. RT-PCR analysis of cells isolated from atrophied muscles indicated that several mRNA characteristic of the myogenic program in MPC were absent. Cells isolated from atrophied muscles failed to properly proliferate and undergo differentiation into multinucleated myotubes. Thus atrophy led to a decrease in MPC and caused dysfunction in those MPC that remained. Upon regrowth of the atrophied muscles, these deleterious effects were reversed. Our data suggest that preventing loss or dysfunction of MPC may be a new pharmacological target during muscle atrophy.
Muscle atrophy is common in the elderly. However, the etiologic role of muscle atrophy associated with osteoarthritis of the knee has not been studied in detail. We assessed the association between age-related muscle atrophy around the knee joint and incident radiographic osteoarthritis of the knee. Twenty-one women in their thirties and 17 women in their sixties participated. They had no history, symptoms, or objective findings of any knee problems, and none of the participants was limited in performing daily activities. Radiographs of the knee joint were graded for the presence of osteoarthritis, and the cross-sectional imaging around the knee joint was carried out using computed tomography. Incident radiographic osteoarthritis was observed in 6 of the 17 women in their sixties. Quadriceps-dominant muscle atrophy was marked in the elderly women with radiographic osteoarthritis. In a multivariate analysis, the risk of incident radiographic osteoarthritis of the knee was significantly increased among women with a higher hamstrings/quadriceps cross-sectional area ratio. The results suggest the possibility that age-related quadriceps-dominant muscle atrophy may play a role in the pathogenesis of osteoarthritis of the knee.
Skeletal muscle fibres are multinucleate syncitial cells that change size during adult life depending on functional demand. The relative contribution of change in nuclear number and/or cell growth to fibre size change is unclear. We report that nuclei/unit length decreases in larger fibres during skeletal muscle ageing. This leads to an increased size of nuclear domain (quantity of cytoplasm/number of nuclei within that cytoplasm). Initially, larger fibres have more satellite cells than small fibres, but this advantage is lost as satellite cells decline with age. These changes are accompanied by an overall decline in fibre size, returning domain size to the normal range. Exacerbated loss of fibre nuclei per unit length during ageing of myoD-null mice provides the first experimental support for the hypothesis that a satellite cell defect causes inadequate nuclear replacement. We propose a model in which a decline in satellite cell function and/or number during ageing leads to a loss of nuclei from large fibres and an associated domain size increase that triggers cytoplasmic atrophy through the normal cell-size-regulating machinery.